Publications by year
In Press
Short PJ, McRae JF, Gallone G, Sifrim A, Won H, Geschwind DH, Wright CF, Firth HV, FitzPatrick DR, Barrett JC, et al (In Press). <i>De novo</i> mutations in regulatory elements cause neurodevelopmental disorders.
Abstract:
De novo mutations in regulatory elements cause neurodevelopmental disorders
SummaryDe novo mutations in hundreds of different genes collectively cause 25-42% of severe developmental disorders (DD). The cause in the remaining cases is largely unknown. The role of de novo mutations in regulatory elements affecting known DD associated genes or other genes is essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 DD patients. Here we show that de novo mutations in highly conserved fetal-brain active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant two-fold enrichment of recurrently mutated elements. We estimate that, genome-wide, de novo mutations in fetaLbrain active elements are likely to be causal for 1-3% of patients without a diagnostic coding variant and that only a small fraction (<2%) of de novo mutations in these elements are pathogenic. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasise the importance of combining functional and evolutionary evidence to delineate regulatory causes of genetic disorders.
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Gunning AC, Fryer V, Fasham J, Crosby AH, Ellard S, Baple E, Wright CF (In Press). Assessing performance of pathogenicity predictors using clinically-relevant variant datasets.
Abstract:
Assessing performance of pathogenicity predictors using clinically-relevant variant datasets
ABSTRACTPurposePathogenicity predictors are an integral part of genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically-relevant dataset has not been undertaken.MethodsWe derive two validation datasets: an “open” dataset containing variants extracted from publicly-available databases, similar to those commonly applied in previous benchmarking exercises, and a “clinically-representative” dataset containing variants identified through research/diagnostic exome and diagnostic panel sequencing. Using these datasets, we evaluate the performance of three recently developed meta-predictors, REVEL, GAVIN and ClinPred, and compare their performance against two commonly used in silico tools, SIFT and PolyPhen-2.ResultsAlthough the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically-representative dataset. Using our clinically-relevant dataset, REVEL performed best with an area under the ROC of 0.81. Using a concordance-based approach based on a consensus of multiple tools reduces the performance due to both discordance between tools and false concordance where tools make common misclassification. Analysis of tool feature usage may give an insight into the tool performance and misclassification.ConclusionOur results support the adoption of meta-predictors over traditional in silico tools, but do not support a consensus-based approach as recommended by current variant classification guidelines.
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Weedon MN, Jackson L, Harrison JW, Ruth KS, Tyrrell J, Hattersley AT, Wright CF (In Press). Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing.
Abstract:
Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing
ABSTRACTObjectivesTo determine the analytical validity of SNP-chips for genotyping very rare genetic variants.DesignRetrospective study using data from two publicly available resources, the UK Biobank and the Personal Genome Project.SettingResearch biobanks and direct-to-consumer genetic testing in the UK and USA.Participants49,908 individuals recruited to UK Biobank, and 21 individuals who purchased consumer genetic tests and shared their data online via the Personal Genomes Project.Main outcome measuresWe assessed the analytical validity of genotypes from SNP-chips (index test) with sequencing data (reference standard). We evaluated the genotyping accuracy of the SNP-chips and split the results by variant frequency. We went on to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis of clinically-actionable variants in UK Biobank, and assessed BRCA-related cancers (breast, ovarian, prostate and pancreatic) in participants using cancer registry data.ResultsSNP-chip genotype accuracy is high overall; sensitivity, specificity and precision are all >99% for 108,574 common variants directly genotyped by the UK Biobank SNP-chips. However, the likelihood of a true positive result reduces dramatically with decreasing variant frequency; for variants with a frequency <0.001% in UK Biobank the precision is very low and only 16% of 4,711 variants from the SNP-chips confirm with sequencing data. Results are similar for SNP-chip data from the Personal Genomes Project, and 20/21 individuals have at least one rare pathogenic variant that has been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are sensitivity 34.6%, specificity 98.3% and precision 4.2%. Rates of BRCA-related cancers in individuals in UK Biobank with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98 to 1.67), while sequence-positive individuals have a significantly increased risk (OR 3.73, P=3.5×10−12, 95% CI: 2.57 to 5.40).ConclusionSNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.SUMMARY BOXSection 1: What is already known on this topicSNP-chips are an accurate and affordable method for genotyping common genetic variants across the genome. They are often used by direct-to-consumer (DTC) genetic testing companies and research studies, but there several case reports suggesting they perform poorly for genotyping rare genetic variants when compared with sequencing.Section 2: What this study addsOur study confirms that SNP-chips are highly inaccurate for genotyping rare, clinically-actionable variants. Using large-scale SNP-chip and sequencing data from UK Biobank, we show that SNP-chips have a very low precision of <16% for detecting very rare variants (i.e. the majority of variants with population frequency of <0.001% are false positives). We observed a similar performance in a small sample of raw SNP-chip data from DTC genetic tests. Very rare variants assayed using SNP-chips should not be used to guide health decisions without validation.
Abstract.
Niemi MEK, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, McAloney K, McRae J, Radford EJ, Yu S, et al (In Press). Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
Abstract:
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders
There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1. However, patients with the same genetic defect can have different clinical presentation 2–4, and some individuals carrying known disease-causing variants can appear unaffected 5. What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.
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Gardner EJ, Sifrim A, Lindsay SJ, Prigmore E, Rajan D, Danecek P, Gallone G, Eberhardt RY, Martin HC, Wright CF, et al (In Press). Detecting cryptic clinically-relevant structural variation in exome sequencing data increases diagnostic yield for developmental disorders.
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Detecting cryptic clinically-relevant structural variation in exome sequencing data increases diagnostic yield for developmental disorders
SummaryStructural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool ‘InDelible’, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.
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Eberhardt RY, Wright CF, FitzPatrick DR, Hurles ME, Firth HV (In Press). Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study.
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Detection of mosaic chromosomal alterations in children with severe developmental disorders recruited to the DDD study
ABSTRACTPurposeStructural mosaicism has been previously implicated in developmental disorders. We aim to identify rare mosaic chromosomal alterations (MCAs) in probands with severe undiagnosed developmental disorders.MethodsWe identified MCAs in SNP array data from 12,530 probands in the Deciphering Developmental Disorders (DDD) study using MoChA.ResultsWe found 61 MCAs in 57 probands, many of these were tissue specific. In 23/26 (88.5%) cases for which the MCA was detected in saliva where blood was also available for analysis, the MCA could not be detected in blood. The MCAs included 20 polysomies, comprising either one arm of a chromosome or a whole chromosome, for which we were able to show the timing of the error (25% mitosis, 40% meiosis I, 35% meiosis II). Only 2/57 (3.5%) of the probands in whom we found MCAs had another likely genetic diagnosis identified by whole exome sequencing, despite an overall diagnostic yield of ∼40% across the cohort.ConclusionOur results show that identification of MCAs provides candidate diagnoses for previously undiagnosed patients with developmental disorders, potentially explaining ∼0.45% of cases in the DDD study. Nearly 90% of these MCAs would have remained undetected by analysing DNA from blood and no other tissue.
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Laver TW, Wakeling MN, Knox O, Colclough K, Wright CF, Ellard S, Hattersley AT, Weedon MN, Patel KA (In Press). Evaluation of evidence for pathogenicity demonstrates that<i>BLK, KLF11</i>and<i>PAX4</i>should not be included in diagnostic testing for MODY.
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Evaluation of evidence for pathogenicity demonstrates thatBLK, KLF11andPAX4should not be included in diagnostic testing for MODY
AbstractMaturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants inBLK(MODY11),KLF11(MODY7) andPAX4(MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY,HNF1AandHNF4A. The published variants inBLK, KLF11andPAX4showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared toHNF1AandHNF4A(LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95×10−5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVsP>0.05, missenseP>0.1 for all three genes) whileHNF1AandHNF4Awere enriched (P<10−6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not supportBLK, KLF11orPAX4as causes of MODY. They should not be included in MODY diagnostic genetic testing.
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Cannon S, Williams M, Gunning AC, Wright CF (In Press). Evaluation of<i>in silico</i>pathogenicity prediction tools for the classification of small in-frame indels.
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Evaluation ofin silicopathogenicity prediction tools for the classification of small in-frame indels
ABSTRACTBackgroundThe use ofin silicopathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied.MethodsWe created a dataset of 3964 small (<100bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1-5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2 PROVEAN, SIFT-indel, VEST-indel and VVP.ResultsOur dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n=809), ClinVar (n=2882) and, DDD (n=273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81-0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools’ training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64-0.87. Overall, VEST-indel performed best, with AUCs of 0.93 (full dataset) and 0.87 (DDD subset).ConclusionsAlgorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.
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Zhang X, Theotokis PI, Li N, Wright CF, Samocha KE, Whiffin N, Ware JS (In Press). Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery.
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Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery
AbstractThe clinical impact of most germline missense variants in humans remains unknown. Genetic constraint identifies genomic regions under negative selection, where variations likely have functional impacts, but the spatial resolution of existing constraint metrics is limited. Here we present the Homologous Missense Constraint (HMC) score, which measures genetic constraint at quasi single amino-acid resolution by aggregating signals across protein homologues. We identify one million possible missense variants under strong negative selection. HMC precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD), and is orthogonal to these, adding power when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly-significant associated with DD that could act through an altered-function mechanism. Overall, HMC is a novel and strong predictor to improve missense variant interpretation.
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Aitken S, Firth HV, Wright CF, Hurles ME, FitzPatrick DR, Semple CA (In Press). IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders.
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IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders
SummaryDiagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenotype Resources Optimises Variant Evaluation in Developmental Disorders (IMPROVE-DD) by incorporating additional classes of data commonly available to clinicians and recorded in health records. In doing so, we quantify the distinct contributions of gender, growth, and development in addition to Human Phenotype Ontology (HPO) terms, and demonstrate added value from these readily-available information sources. We use likelihood ratios for nominal and quantitative data and propose a novel classifier for HPO terms in this framework. This Bayesian framework results in more robust diagnoses. Using data systematically collected in the DDD study, we considered 77 genes with pathogenic/likely pathogenic variants in >10 probands. All genes showed at least a satisfactory prediction by ROC when testing on training data (AUC≥0.6), and HPO terms were the best individual predictor for the majority of genes, though a minority (13/77) of genes were better predicted by other phenotypic data types. Overall, classifiers based upon multiple integrated phenotypic data sources performed better than those based upon any individual source, and importantly, integrated models produced notably fewer false positives. Finally, we show that IMPROVE-DD models with good predictive performance on cross-validation can be constructed from relatively few cases. This suggests new strategies for candidate gene prioritisation, and highlights the value of systematic clinical data collection to support diagnostic programmes.
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Wright C (In Press). Improving Genomic Diagnosis of Rare Pediatric Disease in the UK and Ireland.
New England Journal of MedicineAbstract:
Improving Genomic Diagnosis of Rare Pediatric Disease in the UK and Ireland
Background: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genome-wide diagnostic approaches. Finding a molecular diagnosis is challenging but can have lifelong benefits.
Methods: the Deciphering Developmental Disorders (DDD) study recruited >13,500 families with severe, likely monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services around the UK and Ireland. We collected standardised phenotype data and performed exome sequencing and microarray analysis to investigate novel genetic causes. We developed an iterative variant analysis pipeline, reporting candidate variants to clinical teams for validation, diagnostic interpretation and communication to families. We performed multiple regression analyses evaluating factors affecting probability of diagnosis.
Results: We reported ~1 candidate variant per parent-offspring trio and ~2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we achieved a diagnosis in ~41% (5502 probands), of whom ~76% have a pathogenic de novo variant. Another ~22% have variants of uncertain significance in genes robustly linked with monogenic developmental disorders. Recruitment as a parent-offspring trio had the largest impact on chance of diagnosis (OR=4.70). Probands who were extremely premature (OR=0.39), had in-utero exposure to antiepileptic medications (OR=0.44), or whose mothers had diabetes (OR=0.52) were less likely to be diagnosed, as were those of African ancestry (OR=0.51).
Conclusions: the DDD study shows multimodal analysis of genome-wide data has good diagnostic power, even after prior attempts at diagnosis.
(Funded by Wellcome Trust and others.)
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Jackson L, Weedon MN, Harrison JW, Wood AR, Ruth KS, Tyrrell J, Wright CF (In Press). Influence of family history on penetrance of hereditary cancers in a population setting.
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Influence of family history on penetrance of hereditary cancers in a population setting
AbstractBackgroundWe sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort.MethodsWe analysed 454,712 UK Biobank participants with exome sequence and clinical data. We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for age, sex, death, recruitment centre, screening and prophylactic surgery).ResultsWomen with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was significantly higher in those with a first-degree family history (relative hazard 10.29 and 7.82, respectively) than those without (7.82 and 4.66). Penetrance to age 60 was also higher in those with a family history (44.7% and 24.1%) versus those without (22.8% and 17.9%). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of bowel cancer that was significantly higher in those with a family history (relative hazard 63.7, 68.4 and 12.1) than those without (20.9, 18.6 and 5.9). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (27.1% and 25.2%) versus those without (15.2% and 3.2%).ConclusionsIndividuals with pathogenic cancer syndrome variants are at significantly less elevated risk of cancer in the absence of family history (risk ratio 0.57), so invasive follow-up may be unwarranted.
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Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, Gallone G, Lelieveld SH, Martin HC, McRae JF, et al (In Press). Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders.
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Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders
SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
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Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, Gallone G, Lelieveld SH, Martin HC, McRae JF, et al (In Press). Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders.
Abstract:
Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders
SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 299 significantly DD-associated genes, including 49 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 500 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
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Wright C, Tuke M, Frayling T, Weedon M, Murray A, Tyrrell J, Ruth K, Beaumont R, Wood A (In Press). Large copy number variants in UK Biobank caused by clonal haematopoiesis may confound penetrance estimates. American Journal of Human Genetics
Wright CF, Quaife NM, Ramos-Hernández L, Danecek P, Ferla MP, Samocha KE, Kaplanis J, Gardner EJ, Eberhardt RY, Chao KR, et al (In Press). Non-coding variants upstream of<i>MEF2C</i>cause severe developmental disorder through three distinct loss-of-function mechanisms.
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Non-coding variants upstream ofMEF2Ccause severe developmental disorder through three distinct loss-of-function mechanisms
AbstractClinical genetic testing of protein-coding regions identifies a likely causative variant in only ∼35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study forde novomutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream ofMEF2Cthat cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified inMEF2Cin the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5’UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.
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Wright CF, Campbell P, Eberhardt RY, Aitken S, Perrett D, Brent S, Danecek P, Gardner EJ, Chundru VK, Lindsay SJ, et al (In Press). Optimising diagnostic yield in highly penetrant genomic disease.
Abstract:
Optimising diagnostic yield in highly penetrant genomic disease
ABSTRACTBackgroundPediatric disorders include a range of highly genetically heterogeneous conditions that are amenable to genome-wide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits.MethodsThe Deciphering Developmental Disorders (DDD) study recruited >33,500 individuals from families with severe, likely monogenic developmental disorders from 24 regional genetics services around the UK and Ireland. We collected detailed standardised phenotype data and performed whole-exome sequencing and microarray analysis to investigate novel genetic causes. We developed an augmented variant analysis and re-analysis pipeline to maximise sensitivity and specificity, and communicated candidate variants to clinical teams for validation and diagnostic interpretation. We performed multiple regression analyses to evaluate factors affecting the probability of being diagnosed.ResultsWe reported approximately one candidate variant per parent-offspring trio and 2.5 variants per singleton proband, including both sequence and structural variants. Using clinical and computational approaches to variant classification, we have achieved a diagnosis in at least 34% (4507 probands), of whom 67% have a pathogenicde novomutation. Being recruited as a parent-offspring trio had the largest impact on the chance of being diagnosed (OR=4.70). Probands who were extremely premature (OR=0.39), hadin uteroexposure to antiepileptic medications (OR=0.44), or whose mothers had diabetes (OR=0.52) were less likely to be diagnosed, as were those of African ancestry (OR=0.51).ConclusionsOptimising diagnosis and discovery in highly penetrant genomic disease depends upon ongoing and novel scientific analyses, ethical recruitment and feedback policies, and collaborative clinical-research partnerships.
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Lord J, Gallone G, Short PJ, McRae JF, Ironfield H, Wynn EH, Gerety SS, He L, Kerr B, Johnson DS, et al (In Press). Pathogenicity and selective constraint on variation near splice sites.
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Pathogenicity and selective constraint on variation near splice sites
AbstractMutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.
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De Franco E, Owens NDL, Montaser H, Wakeling MN, Saarimäki-Vire J, Ibrahim H, Triantou A, Balboa D, Caswell RC, Johnson MB, et al (In Press). Primate-specific ZNF808 is essential for pancreatic development in humans.
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Primate-specific ZNF808 is essential for pancreatic development in humans
SummaryIdentifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. Here we report the identification of homozygous loss of function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of many transposable elements it normally represses during early pancreas development. This results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. We show that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.
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Kingdom R, Tuke M, Wood A, Beaumont R, Frayling T, Weedon M, Wright C (In Press). Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population.
American Journal of Human GeneticsAbstract:
Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population
Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same variants can also be found in people without the associated clinical phenotypes. The penetrance of these monogenic variants is generally unknown in the wider population, as they are typically identified in small clinical cohorts of affected individuals and families with highly penetrant variants. Here, we investigated the phenotypic effect of rare, potentially deleterious variants in genes and loci where similar variants are known to cause monogenic developmental disorders (DD) in a large population cohort. We used UK Biobank to investigate phenotypes associated with rare protein-truncating and missense variants in 599 monoallelic DDG2P genes using whole exome sequencing data from ~200,000 individuals, and rare copy number variants overlapping known DD loci using SNP-array data from ~500,000 individuals. We found that individuals with these likely deleterious variants had a mild DD-related phenotype, including lower fluid intelligence, slower reaction times, lower numeric memory scores and longer pairs matching times compared to the rest of the UK Biobank cohort. They were also shorter, with a higher BMI and had significant socioeconomic disadvantages, being less likely to be employed or be able to work, and having a lower income and higher deprivation index. Our findings suggest that many genes routinely tested within paediatric genetics have deleterious variants with intermediate penetrance that may cause lifelong milder, sub-clinical phenotypes in the general adult population.
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Copeland H, Kivuva E, Firth H, Wright C (In Press). Systematic assessment of outcomes following a genetic diagnosis identified through a large-scale research study into developmental disorders. Genetics in Medicine
Copeland H, Kivuva E, Firth HV, Wright CF (In Press). Systematic assessment of outcomes following a genetic diagnosis identified through a large-scale research study into developmental disorders.
Abstract:
Systematic assessment of outcomes following a genetic diagnosis identified through a large-scale research study into developmental disorders
AbstractPurposeThe clinical and psychosocial outcomes associated with receiving a genetic diagnosis for developmental disorders are wide-ranging but under-studied. We sought to investigate outcomes from a subset of families who received a diagnosis through the Deciphering Developmental Disorders (DDD) study.MethodIndividuals recruited through the Peninsula Clinical Genetics Service who received a confirmed genetic diagnosis through the DDD study before August 2019 (n=112) were included in a clinical audit. Families with no identified clinical outcomes (n=16) were invited to participate in semi-structured telephone interviews.ResultsDisease-specific treatment was identified for seven probands (6%), while 48 probands (43%) were referred for further investigations or screening and 60 probands (54%) were recruited to further research. Just five families (4%) opted for prenatal testing in a subsequent pregnancy, reflecting the relatively advanced maternal age in our cohort, and 42 families (38%) were given disease-specific information or signposting to patient-specific resources such as support groups. Six interviews were performed (response rate=47%) and thematic analysis identified four major themes: reaching a diagnosis, emotional impact, family implications and practical issues.ConclusionsOur data demonstrate that receiving a genetic diagnosis has substantial positive medical and psychosocial outcomes for the majority of patients and their families.
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Martin HC, Gardner EJ, Samocha KE, Kaplanis J, Akawi N, Sifrim A, Eberhardt RY, Tavares ALT, Neville MDC, Niemi MEK, et al (In Press). The contribution of X-linked coding variation to severe developmental disorders.
Abstract:
The contribution of X-linked coding variation to severe developmental disorders
AbstractOver 130 X-linked genes have been robustly associated with developmental disorders (DDs), and X-linked causes have been hypothesised to underlie the higher DD rates in males. We evaluated the burden of X-linked coding variation in 11,046 DD patients, and found a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We developed an improved strategy to detect novel X-linked DDs and identified 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known DD-associated genes. Importantly, we estimated that, in male probands, only 13% of inherited rare missense variants in known DD-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.
Abstract.
Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM, et al (In Press). The penetrance of age-related monogenic disease depends on ascertainment context.
Abstract:
The penetrance of age-related monogenic disease depends on ascertainment context
AbstractBACKGROUNDAccurate penetrance of monogenic disorders is often unknown due to a phenotype-first approach to genetic testing. Here, we use a genotype-first approach in four large cohorts with different ascertainment contexts to accurately estimate penetrance of the three commonest causes of monogenic diabetes, Maturity Onset Diabetes of the Young (MODY). We contrast HNF1A-MODY / HNF4A-MODY which causes an age-related progressive diabetes and GCK-MODY, which causes life-long mild hyperglycaemia.METHODSWe analysed clinical and genetic sequencing data from four different cohorts: 1742 probands referred for clinical MODY testing; 2194 family members of the MODY probands; 132,194 individuals from an American hospital-based cohort; and 198,748 individuals from a UK population-based cohort.RESULTSAge-related penetrance of diabetes for pathogenic variants in HNF1A and HNF4A was substantially lower in the clinically unselected cohorts compared to clinically referred probands (ranging from 32% to 98% at age 40yrs for HNF1A, and 21% to 99% for HNF4A). The background rate of diabetes, but not clinical features or variant type, explained the reduced penetrance in the unselected cohorts. In contrast, penetrance of mild hyperglycaemia for pathogenic GCK variants was similarly high across cohorts (ranging from 89 to 97%) despite substantial variation in the background rates of diabetes.CONCLUSIONSAscertainment context is crucial when interpreting the consequences of monogenic variants for age-related variably penetrant disorders. This finding has important implications for opportunistic screening during genomic testing.
Abstract.
Weedon M, Jackson L, Harrison J, Ruth K, Tyrrell J, Hattersley A, Wright C (In Press). Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ: British Medical Journal
Caswell RC, Owens MM, Gunning AC, Ellard S, Wright CF (In Press). Using structural analysis <i>in silico</i> to assess the impact of missense variants in MEN1.
Abstract:
Using structural analysis in silico to assess the impact of missense variants in MEN1
ABSTRACTDespite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variation, the interpretation of novel missense variants can remain challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease-associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analysed the predicted effect of 338 known missense variants on the structure of Menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability providing a strong indicator of pathogenicity. Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise Menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease.
Abstract.
Thormann A, Halachev M, McLaren W, Moore DJ, Svinti V, Campbell A, Kerr SM, Hunt S, Dunlop MG, Hurles ME, et al (In Press). VEP-G2P: a Tool for Efficient, Flexible and Scalable Diagnostic Filtering of Genomic Variants.
Abstract:
VEP-G2P: a Tool for Efficient, Flexible and Scalable Diagnostic Filtering of Genomic Variants
AbstractPurposeWe aimed to develop an efficient, flexible, scalable and evidence-based approach to sequence-based diagnostic analysis/re-analysis of conditions with very large numbers of different causative genes. We then wished to define the expected rate of plausibly causative variants coming through strict filtering in control in comparison to disease populations to quantify background diagnostic “noise”.MethodsWe developed G2P (www.ebi.ac.uk/gene2phenotype) as an online system to facilitate the development, validation, curation and distribution of large-scale, evidence-based datasets for use in diagnostic variant filtering. Each locus-genotype-mechanism-disease-evidence thread (LGMDET) associates an allelic requirement and a mutational consequence at a defined locus with a disease entity and a confidence level and evidence links. We then developed an extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P, which can filter based on G2P other widely used gene panel curation systems. We compared the output of disease-associated and control whole exome sequence (WES) using Developmental Disorders G2P (G2PDD; 2044 LGMDETs) and constitutional cancer predisposition G2P (G2PCancer; 128 LGMDETs).ResultsWe have shown a sensitivity/precision of 97.3%/33% and 81.6%/22.7% for causative de novo and inherited variants respectively using VEP-G2PDD in DDD study probands WES. Many of the apparently diagnostic genotypes “missed” are likely false-positive reports with lower minor allele frequencies and more severe predicted consequences being diagnostically-discriminative features.ConclusionCase:control comparisons using VEP-G2PDD established an observed:expected ratio of 1:30,000 plausibly causative variants in proband WES to ~1:40,000 reportable but presumed-benign variants in controls. At least half the filtered variants in probands represent background “noise”. Supporting phenotypic evidence is, therefore, necessary in genetically-heterogeneous disorders. G2P and VEP-G2P provides a practical approach to optimize disease-specific filtering parameters in diagnostic genetic research.
Abstract.
Wright C, Parker M, Lucassen A (In Press). When genomic medicine reveals misattributed genetic relationships – the debate about disclosure revisited. Genetics in Medicine
2023
Cannon S, Williams M, Gunning AC, Wright CF (2023). Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels.
BMC Medical Genomics,
16(1).
Abstract:
Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels
Abstract
. Background
. The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied.
.
. Methods
. We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1–5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP.
.
. Results
. Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81–0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools’ training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64–0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset).
.
. Conclusions
. Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.
.
Abstract.
Aitken S, Firth HV, Wright CF, Hurles ME, FitzPatrick DR, Semple CA (2023). IMPROVE-DD: Integrating multiple phenotype resources optimizes variant evaluation in genetically determined developmental disorders.
HGG Adv,
4(1).
Abstract:
IMPROVE-DD: Integrating multiple phenotype resources optimizes variant evaluation in genetically determined developmental disorders.
Diagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenotype Resources Optimizes Variant Evaluation in Developmental Disorders (IMPROVE-DD) by incorporating additional classes of data commonly available to clinicians and recorded in health records. In doing so, we quantify the distinct contributions of sex, growth, and development in addition to Human Phenotype Ontology (HPO) terms and demonstrate added value from these readily available information sources. We use likelihood ratios for nominal and quantitative data and propose a classifier for HPO terms in this framework. This Bayesian framework results in more robust diagnoses. Using data systematically collected in the Deciphering Developmental Disorders study, we considered 77 genes with pathogenic/likely pathogenic variants in ≥10 individuals. All genes showed at least a satisfactory prediction by receiver operating characteristic when testing on training data (AUC ≥ 0.6), and HPO terms were the best predictor for the majority of genes, though a minority (13/77) of genes were better predicted by other phenotypic data types. Overall, classifiers based upon multiple integrated phenotypic data sources performed better than those based upon any individual source, and importantly, integrated models produced notably fewer false positives. Finally, we show that IMPROVE-DD models with good predictive performance on cross-validation can be constructed from relatively few individuals. This suggests new strategies for candidate gene prioritization and highlights the value of systematic clinical data collection to support diagnostic programs.
Abstract.
Author URL.
Wright CF, FitzPatrick DR, Ware JS, Rehm HL, Firth HV (2023). Importance of adopting standardized MANE transcripts in clinical reporting.
Genet Med,
25(2).
Author URL.
2022
Caswell RC, Gunning AC, Owens MM, Ellard S, Wright CF (2022). Assessing the clinical utility of protein structural analysis in genomic variant classification: experiences from a diagnostic laboratory.
GENOME MEDICINE,
14(1).
Author URL.
Wright CF, Prigmore E, Rajan D, Handsaker J, McRae J, Kaplanis J, Fitzgerald TW, FitzPatrick DR, Firth HV, Hurles ME, et al (2022). Author Correction: Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data.
Nat Commun,
13(1).
Author URL.
Beaumont RN, Wright CF (2022). Estimating diagnostic noise in panel-based genomic analysis.
Beaumont RN, Wright CF (2022). Estimating diagnostic noise in panel-based genomic analysis.
Genet Med,
24(10), 2042-2050.
Abstract:
Estimating diagnostic noise in panel-based genomic analysis.
PURPOSE: Gene panels with a series of strict variant filtering rules are often used for clinical analysis of exomes and genomes. Panel sizes vary, affecting the test's sensitivity and specificity. We investigated the background rate of candidate variants in a population setting using gene panels developed to diagnose a range of heterogeneous monogenic diseases. METHODS: We used the Gene2Phenotype database with the Variant Effect Predictor plugin to identify rare nonsynonymous variants in exome sequence data from 200,643 individuals in UK Biobank. We evaluated 5 clinically curated gene panels of varying sizes (50-1700 genes). RESULTS: Bigger gene panels resulted in more prioritized variants, varying from an average of approximately 0.3 to 3.5 variants per person. The number of individuals with prioritized variants varied linearly with coding sequence length for monoallelic genes (∼300 individuals per 1000 base pairs) and quadratically for biallelic genes, with notable outliers. CONCLUSION: Although large gene panels may be the best strategy to maximize diagnostic yield in genetically heterogeneous diseases, they frequently prioritize likely benign variants requiring follow up. Most individuals have ≥1 rare nonsynonymous variant in panels containing >500 disease genes. Extreme caution should be applied when interpreting candidate variants, particularly in the absence of relevant phenotypes.
Abstract.
Author URL.
Laver TW, Wakeling MN, Knox O, Colclough K, Wright CF, Ellard S, Hattersley AT, Weedon MN, Patel KA (2022). Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not be Included in Diagnostic Testing for MODY.
Diabetes,
71(5), 1128-1136.
Abstract:
Evaluation of Evidence for Pathogenicity Demonstrates That BLK, KLF11, and PAX4 Should Not be Included in Diagnostic Testing for MODY.
Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7), and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (cosegregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n = 1,227) compared with a control population (UK Biobank [n = 185,898]). For comparison we analyzed well-established causes of MODY, HNF1A, and HNF4A. The published variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (combined logarithm of the odds [LOD] scores ≤1.2), compared with HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95 × 10-5). Ultra-rare missense and protein-truncating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV P > 0.05, missense P > 0.1 for all three genes) while HNF1A and HNF4A were enriched (P < 10-6). Findings of sensitivity analyses with different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11, or PAX4 as a cause of MODY. They should not be included in MODY diagnostic genetic testing.
Abstract.
Author URL.
Sörmann J, Schewe M, Proks P, Jouen-Tachoire T, Rao S, Riel EB, Agre KE, Begtrup A, Dean J, Descartes M, et al (2022). Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.
Nat Genet,
54(10), 1534-1543.
Abstract:
Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.
Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.
Abstract.
Author URL.
Kingdom R, Beaumont RN, Wood AR, Weedon MN, Wright CF (2022). Genetic modifiers of rare variants in monogenic developmental disorder loci.
Shekari S, Stankovic S, Huang QQ, Gardner EJ, Owens NDL, Azad A, Hawkes G, Kentistou KA, Beaumont RN, Day FR, et al (2022). Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring.
Kingdom R, Wright CF (2022). Incomplete Penetrance and Variable Expressivity: from Clinical Studies to Population Cohorts.
FRONTIERS IN GENETICS,
13 Author URL.
Shekari S, Stankovic S, Gardner EJ, Hawkes G, Kentistou KA, Beaumont RN, Mörseburg A, Wood AR, Mishra G, Day F, et al (2022). Monogenic causes of Premature Ovarian Insufficiency are rare and mostly recessive.
Ellingford JM, Ahn JW, Bagnall RD, Baralle D, Barton S, Campbell C, Downes K, Ellard S, Duff-Farrier C, FitzPatrick DR, et al (2022). Recommendations for clinical interpretation of variants found in non-coding regions of the genome.
Genome Medicine,
14(1).
Abstract:
Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Abstract
. Background
. The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.
.
. Methods
. We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.
.
. Results
. We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants.
.
. Conclusions
. These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
.
Abstract.
Cannon S, Clissold R, Sukcharoen K, Tuke M, Hawkes G, Beaumont RN, Wood AR, Gilchrist M, Hattersley AT, Oram RA, et al (2022). Recurrent 17q12 microduplications contribute to renal disease but not diabetes.
Journal of Medical GeneticsAbstract:
Recurrent 17q12 microduplications contribute to renal disease but not diabetes
Background17q12 microdeletion and microduplication syndromes present as overlapping, multisystem disorders. We assessed the disease phenotypes of individuals with 17q12 CNV in a population-based cohort.MethodsWe investigated 17q12 CNV using microarray data from 450 993 individuals in the UK Biobank and calculated disease status associations for diabetes, liver and renal function, neurological and psychiatric traits.ResultsWe identified 11 17q12 microdeletions and 106 microduplications. Microdeletions were strongly associated with diabetes (p=2×10−7) but microduplications were not. Estimated glomerular filtration rate (eGFR mL/min/1.73 m2) was consistently lower in individuals with microdeletions (p=3×10−12) and microduplications (p=6×10−25). Similarly, eGFR <60, including end-stage renal disease, was associated with microdeletions (p=2×10−9, p<0.003) and microduplications (p=1×10−9, p=0.009), respectively, highlighting sometimes substantially reduced renal function in each. Microduplications were associated with decreased fluid intelligence (p=3×10−4). SNP association analysis in the 17q12 region implicated changes to HNF1B as causing decreased eGFR (NC_000017.11:g.37741642T>G, rs12601991, p=4×10−21) and diabetes (NC_000017.11:g.37741165C>T, rs7501939, p=6×10−17). A second locus within the region was also associated with fluid intelligence (NC_000017.11:g.36593168T>C, rs1005552, p=6×10−9) and decreased eGFR (NC_000017.11:g.36558947T>C, rs12150665, p=4×10–15).ConclusionWe demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort, likely caused by HNF1B haploinsufficiency. We show that both 17q12 microdeletions and microduplications are associated with renal disease, and multiple genes within the region likely contribute to renal and neurocognitive phenotypes.
Abstract.
Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM, et al (2022). Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.
Am J Hum Genet,
109(11), 2018-2028.
Abstract:
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.
The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list.
Abstract.
Author URL.
DiStefano MT, Goehringer S, Babb L, Alkuraya FS, Amberger J, Amin M, Austin-Tse C, Balzotti M, Berg JS, Birney E, et al (2022). The Gene Curation Coalition: a global effort to harmonize gene-disease evidence resources.
Genet Med,
24(8), 1732-1742.
Abstract:
The Gene Curation Coalition: a global effort to harmonize gene-disease evidence resources.
PURPOSE: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS: the GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS: on the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.
Abstract.
Author URL.
2021
Smedley D, Smith KR, Martin A, Thomas EA, McDonagh EM, Cipriani V, Ellingford JM, Arno G, Tucci A, Vandrovcova J, et al (2021). 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report. New England Journal of Medicine, 385(20), 1868-1880.
Beaumont RN, Mayne IK, Freathy RM, Wright CF (2021). Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders.
Human Molecular Genetics,
30(11), 1057-1066.
Abstract:
Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders
Abstract
. Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.
Abstract.
Gardner EJ, Sifrim A, Lindsay SJ, Prigmore E, Rajan D, Danecek P, Gallone G, Eberhardt RY, Martin HC, Wright CF, et al (2021). Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for developmental disorders.
Am J Hum Genet,
108(11), 2186-2194.
Abstract:
Detecting cryptic clinically relevant structural variation in exome-sequencing data increases diagnostic yield for developmental disorders.
Structural variation (SV) describes a broad class of genetic variation greater than 50 bp in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DDs). Individuals presenting with DDs are often referred for diagnostic testing with chromosomal microarrays (CMAs) to identify large copy-number variants (CNVs) and/or with single-gene, gene-panel, or exome sequencing (ES) to identify single-nucleotide variants, small insertions/deletions, and CNVs. However, individuals with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the tool InDelible, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DDs recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 63 rare, damaging variants in genes previously associated with DDs missed by standard SNV, indel, or CNV discovery approaches. Clinical review of these 63 variants determined that about half (30/63) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21 and 500 bp in size and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.9%. of particular interest were seven confirmed de novo variants in MECP2, which represent 35.0% of all de novo protein-truncating variants in MECP2 among DDD study participants. InDelible provides a framework for the discovery of pathogenic SVs that are most likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.
Abstract.
Author URL.
Wright CF, Eberhardt RY, Constantinou P, Hurles ME, FitzPatrick DR, Firth HV (2021). Evaluating variants classified as pathogenic in ClinVar in the DDD Study.
Genetics in Medicine,
23(3), 571-575.
Abstract:
Evaluating variants classified as pathogenic in ClinVar in the DDD Study
Purpose: Automated variant filtering is an essential part of diagnostic genome-wide sequencing but may generate false negative results. We sought to investigate whether some previously identified pathogenic variants may be being routinely excluded by standard variant filtering pipelines. Methods: We evaluated variants that were previously classified as pathogenic or likely pathogenic in ClinVar in known developmental disorder genes using exome sequence data from the Deciphering Developmental Disorders (DDD) study. Results: of these ClinVar pathogenic variants, 3.6% were identified among 13,462 DDD probands, and 1134/1352 (83.9%) had already been independently communicated to clinicians using DDD variant filtering pipelines as plausibly pathogenic. The remaining 218 variants failed consequence, inheritance, or other automated variant filters. Following clinical review of these additional variants, we were able to identify 112 variants in 107 (0.8%) DDD probands as potential diagnoses. Conclusion: Lower minor allele frequency (1 star) are good predictors of a previously identified variant being plausibly diagnostic for developmental disorders. However, around half of previously identified pathogenic variants excluded by automated variant filtering did not appear to be disease-causing, underlining the continued need for clinical evaluation of candidate variants as part of the diagnostic process.
Abstract.
Wright CF, Quaife NM, Ramos-Hernández L, Danecek P, Ferla MP, Samocha KE, Kaplanis J, Gardner EJ, Eberhardt RY, Chao KR, et al (2021). Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.
Am J Hum Genet,
108(6), 1083-1094.
Abstract:
Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms.
Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
Abstract.
Author URL.
Kingdom R, Tuke M, Wood A, Beaumont RN, Frayling T, Weedon MN, Wright CF (2021). Rare genetic variants in dominant developmental disorder loci cause milder related phenotypes in the general population.
Martin HC, Gardner EJ, Samocha KE, Kaplanis J, Akawi N, Sifrim A, Eberhardt RY, Tavares ALT, Neville MDC, Niemi MEK, et al (2021). The contribution of X-linked coding variation to severe developmental disorders.
Nature Communications,
12(1).
Abstract:
The contribution of X-linked coding variation to severe developmental disorders
Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.
Abstract.
Weedon MN, Wright CF, Patel KA, Frayling TM (2021). Unreliability of genotyping arrays for detecting very rare variants in human genetic studies: Example from a recent study of MC4R. Cell, 184(7).
2020
Gunning AC, Fryer V, Fasham J, Crosby AH, Ellard S, Baple EL, Wright CF (2020). Assessing performance of pathogenicity predictors using clinically relevant variant datasets.
Journal of Medical Genetics,
58(8), 547-555.
Abstract:
Assessing performance of pathogenicity predictors using clinically relevant variant datasets
BackgroundPathogenicity predictors are integral to genomic variant interpretation but, despite their widespread usage, an independent validation of performance using a clinically relevant dataset has not been undertaken.MethodsWe derive two validation datasets: an ‘open’ dataset containing variants extracted from publicly available databases, similar to those commonly applied in previous benchmarking exercises, and a ‘clinically representative’ dataset containing variants identified through research/diagnostic exome and panel sequencing. Using these datasets, we evaluate the performance of three recent meta-predictors, REVEL, GAVIN and ClinPred, and compare their performance against two commonly used in silico tools, SIFT and PolyPhen-2.ResultsAlthough the newer meta-predictors outperform the older tools, the performance of all pathogenicity predictors is substantially lower in the clinically representative dataset. Using our clinically relevant dataset, REVEL performed best with an area under the receiver operating characteristic curve of 0.82. Using a concordance-based approach based on a consensus of multiple tools reduces the performance due to both discordance between tools and false concordance where tools make common misclassification. Analysis of tool feature usage may give an insight into the tool performance and misclassification.ConclusionOur results support the adoption of meta-predictors over traditional in silico tools, but do not support a consensus-based approach as in current practice.
Abstract.
Whiffin N, Danecek P, Quaife NM, Kaplanis J, Samocha K, Juusola J, Retterer K, Barton PJR, Firth HV, Hurles ME, et al (2020). De novo noncoding variants upstream of MEF2C cause severe developmental disorders.
Author URL.
Kaplanis J, Samocha KE, Wiel L, Zhang Z, Arvai KJ, Eberhardt RY, Gallone G, Lelieveld SH, Martin HC, McRae JF, et al (2020). Evidence for 28 genetic disorders discovered by combining healthcare and research data.
Nature,
586(7831), 757-762.
Abstract:
Evidence for 28 genetic disorders discovered by combining healthcare and research data
De novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.
Abstract.
Rowe CA, Wright CF (2020). Expanded universal carrier screening and its implementation within a publicly funded healthcare service.
J Community Genet,
11(1), 21-38.
Abstract:
Expanded universal carrier screening and its implementation within a publicly funded healthcare service.
Carrier screening, a well-established clinical initiative, has been slow to take advantage of the new possibilities offered by high-throughput next generation sequencing technologies. There is evidence of significant benefit in expanding carrier screening to include multiple autosomal recessive conditions and offering a 'universal' carrier screen that could be used for a pan-ethnic population. However, the challenges of implementing such a programme and the difficulties of demonstrating efficacy worthy of public health investment are significant barriers. In order for such a programme to be successful, it would need to be applicable and acceptable to the population, which may be ethnically and culturally diverse. There are significant practical and ethical implications associated with determining which variants, genes and conditions to include whilst maintaining adequate sensitivity and accuracy. Although preconception screening would maximise the potential benefits from universal carrier screening, the resource implications of different modes of delivery need to be carefully evaluated and balanced against maximising reproductive autonomy and ensuring equity of access. Currently, although a number of existing initiatives are increasing access to carrier screening, there is insufficient evidence to inform the development of a publicly funded, expanded, universal carrier screening programme that would justify investment over other healthcare interventions.
Abstract.
Author URL.
Gunning AC, Strucinska K, Muñoz Oreja M, Parrish A, Caswell R, Stals KL, Durigon R, Durlacher-Betzer K, Cunningham MH, Grochowski CM, et al (2020). Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.
Am J Hum Genet,
106(2), 272-279.
Abstract:
Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.
Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.
Abstract.
Author URL.
2019
Wright CF, West B, Tuke M, Jones SE, Patel K, Laver TW, Beaumont RN, Tyrrell J, Wood AR, Frayling TM, et al (2019). Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
American Journal of Human Genetics,
104(2), 275-286.
Abstract:
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Abstract.
Wright C, Prigmore E, Rajan D, Handsaker J, McRae J, Kaplanis J, FItzGerald T, FitzPatrick D, Firth H, Hurles M, et al (2019). Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data. Nature Communications, 10
Horton R, Crawford G, Freeman L, Fenwick A, Wright CF, Lucassen A (2019). Direct-to-consumer genetic testing. The BMJ, 367
Kaplanis J, Akawi N, Gallone G, McRae JF, Prigmore E, Wright CF, Fitzpatrick DR, Firth HV, Barrett JC, Hurles ME, et al (2019). Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations.
Genome Res,
29(7), 1047-1056.
Abstract:
Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations.
Approximately 2% of de novo single-nucleotide variants (SNVs) appear as part of clustered mutations that create multinucleotide variants (MNVs). MNVs are an important source of genomic variability as they are more likely to alter an encoded protein than a SNV, which has important implications in disease as well as evolution. Previous studies of MNVs have focused on their mutational origins and have not systematically evaluated their functional impact and contribution to disease. We identified 69,940 MNVs and 91 de novo MNVs in 6688 exome-sequenced parent-offspring trios from the Deciphering Developmental Disorders Study comprising families with severe developmental disorders. We replicated the previously described MNV mutational signatures associated with DNA polymerase zeta, an error-prone translesion polymerase, and the APOBEC family of DNA deaminases. We estimate the simultaneous MNV germline mutation rate to be 1.78 × 10-10 mutations per base pair per generation. We found that most MNVs within a single codon create a missense change that could not have been created by a SNV. MNV-induced missense changes were, on average, more physicochemically divergent, were more depleted in highly constrained genes (pLI ≥ 0.9), and were under stronger purifying selection compared with SNV-induced missense changes. We found that de novo MNVs were significantly enriched in genes previously associated with developmental disorders in affected children. This shows that MNVs can be more damaging than SNVs even when both induce missense changes, and are an important variant type to consider in relation to human disease.
Abstract.
Author URL.
Aitken S, Firth HV, McRae J, Halachev M, Kini U, Parker MJ, Lees MM, Lachlan K, Sarkar A, Joss S, et al (2019). Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.
Am J Hum Genet,
105(5), 933-946.
Abstract:
Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.
Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.
Abstract.
Author URL.
Thormann A, Halachev M, McLaren W, Moore DJ, Svinti V, Campbell A, Kerr SM, Tischkowitz M, Hunt SE, Dunlop MG, et al (2019). Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.
Nat Commun,
10(1).
Abstract:
Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.
We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.
Abstract.
Author URL.
Wright CF, Ware JS, Lucassen AM, Hall A, Middleton A, Rahman N, Ellard S, Firth HV (2019). Genomic variant sharing: a position statement.
Wellcome Open Research,
4, 22-22.
Abstract:
Genomic variant sharing: a position statement
Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.
Abstract.
Wright CF, Ware JS, Lucassen AM, Hall A, Middleton A, Rahman N, Ellard S, Firth HV (2019). Genomic variant sharing: a position statement.
Wellcome Open Research,
4, 22-22.
Abstract:
Genomic variant sharing: a position statement
Sharing de-identified genetic variant data via custom-built online repositories is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, population controls and correlation with clinical context and family history. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of de-identified genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of genetic variants per individual, associated with limited clinical information, should become standard practice in genomic medicine. Information confirming or refuting the role of genetic variants in specific conditions is fundamental scientific knowledge from which everyone has a right to benefit, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for individual clinical interpretation, it may be more appropriate to use a controlled-access model for such data sharing, with the ultimate aim of making as much information available as possible with appropriate governance.
Abstract.
Wright CF, Ware JS, Lucassen AM, Hall A, Middleton A, Rahman N, Ellard S, Firth HV (2019). Genomic variant sharing: a position statement.
Wellcome open research,
4Abstract:
Genomic variant sharing: a position statement.
Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.
Abstract.
Wakeling MN, Laver TW, Wright CF, De Franco E, Stals KL, Patch A-M, Hattersley AT, Flanagan SE, Ellard S, DDD Study, et al (2019). Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease.
Genet Med,
21(4), 982-986.
Abstract:
Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease.
PURPOSE: One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next-generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. METHODS: We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. RESULTS: We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the ten largest regions in a sample. The maximal predictive power is achieved in patients with 3 Mb from a telomere; this gives an area under the curve (AUC) of 0.735 and results in 92% of the causative variants being in one of the ten largest homozygous regions. CONCLUSION: This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.
Abstract.
Author URL.
Lord J, Gallone G, Short PJ, McRae JF, Ironfield H, Wynn EH, Gerety SS, He L, Kerr B, Johnson DS, et al (2019). Pathogenicity and selective constraint on variation near splice sites.
Genome Res,
29(2), 159-170.
Abstract:
Pathogenicity and selective constraint on variation near splice sites.
Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases.
Abstract.
Author URL.
Caswell RC, Owens MM, Gunning AC, Ellard S, Wright CF (2019). Using Structural Analysis in Silico to Assess the Impact of Missense Variants in MEN1.
Journal of the Endocrine Society,
3(12), 2258-2275.
Abstract:
Using Structural Analysis in Silico to Assess the Impact of Missense Variants in MEN1
Abstract
. Despite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variations, the interpretation of novel missense variants remains challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease‒associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analyzed the predicted effect of 338 known missense variants on the structure of menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability, providing a strong indicator of pathogenicity. Subsequent analysis of seven novel missense variants identified during clinical testing of patients with MEN1 showed that all seven were predicted to destabilize menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the effect of missense variants in MEN1 and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease.
Abstract.
2018
Niemi MEK, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, McAloney K, McRae J, Radford EJ, Yu S, et al (2018). Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
Nature,
562(7726), 268-271.
Abstract:
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders.
There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1. However, patients with the same genetic defect can have different clinical presentations2-4, and some individuals who carry known disease-causing variants can appear unaffected5. Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems. Although the genetic causes of these neurodevelopmental disorders are expected to be almost entirely monogenic, we show that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome-wide common variant burden by showing, in an independent sample of 728 trios (comprising a child plus both parents) from the same cohort, that this burden is over-transmitted from parents to children with neurodevelopmental disorders. Our common-variant signal is significantly positively correlated with genetic predisposition to lower educational attainment, decreased intelligence and risk of schizophrenia. We found that common-variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, which suggests that common-variant risk affects patients both with and without a monogenic diagnosis. In addition, previously published common-variant scores for autism, height, birth weight and intracranial volume were all correlated with these traits within our cohort, which suggests that phenotypic expression in individuals with monogenic disorders is affected by the same variants as in the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in neurodevelopmental disorders that are typically considered to be monogenic.
Abstract.
Author URL.
Short PJ, McRae JF, Gallone G, Sifrim A, Won H, Geschwind DH, Wright CF, Firth HV, FitzPatrick DR, Barrett JC, et al (2018). De novo mutations in regulatory elements in neurodevelopmental disorders.
Nature,
555(7698), 611-616.
Abstract:
De novo mutations in regulatory elements in neurodevelopmental disorders.
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.
Abstract.
Author URL.
Faundes V, Newman WG, Bernardini L, Canham N, Clayton-Smith J, Dallapiccola B, Davies SJ, Demos MK, Goldman A, Gill H, et al (2018). Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
Am J Hum Genet,
102(1), 175-187.
Abstract:
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Abstract.
Author URL.
Wright CF, McRae JF, Clayton S, Gallone G, Aitken S, FitzGerald TW, Jones P, Prigmore E, Rajan D, Lord J, et al (2018). Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders.
Genet Med,
20(10), 1216-1223.
Abstract:
Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders.
PURPOSE: Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge. METHODS: We tested this hypothesis in the United Kingdom-wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes. RESULTS: We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder-associated genes discovered since our original publication. CONCLUSION: This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent-offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.
Abstract.
Author URL.
Wright CF, FitzPatrick DR, Firth HV (2018). Paediatric genomics: diagnosing rare disease in children.
Nat Rev Genet,
19(5).
Abstract:
Paediatric genomics: diagnosing rare disease in children.
This corrects the article DOI: 10.1038/nrg.2017.116.
Abstract.
Author URL.
Martin HC, Jones WD, McIntyre R, Sanchez-Andrade G, Sanderson M, Stephenson JD, Jones CP, Handsaker J, Gallone G, Bruntraeger M, et al (2018). Quantifying the contribution of recessive coding variation to developmental disorders.
Science,
362(6419), 1161-1164.
Abstract:
Quantifying the contribution of recessive coding variation to developmental disorders.
We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.
Abstract.
Author URL.
2017
Sadleir LG, Mountier EI, Gill D, Davis S, Joshi C, DeVile C, Kurian MA, DDD Study, Mandelstam S, Wirrell E, et al (2017). Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.
Neurology,
89(10), 1035-1042.
Abstract:
Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.
OBJECTIVE: to define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: a case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.
Abstract.
Author URL.
McRae JF, Clayton S, Fitzgerald TW, Kaplanis J, Prigmore E, Rajan D, Sifrim A, Aitken S, Akawi N, Alvi M, et al (2017). Prevalence and architecture of de novo mutations in developmental disorders.
NATURE,
542(7642), 433-+.
Author URL.
Suri M, Evers JMG, Laskowski RA, O'Brien S, Baker K, Clayton-Smith J, Dabir T, Josifova D, Joss S, Kerr B, et al (2017). Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1.
Mol Genet Genomic Med,
5(5), 495-507.
Abstract:
Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1.
BACKGROUND: Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype-phenotype correlations. METHODS: We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). RESULTS: Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype-phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. CONCLUSION: Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.
Abstract.
Author URL.
Wright CF, Middleton A, Barrett JC, Firth HV, FitzPatrick DR, Hurles M, Parker M (2017). Returning genome sequences to research participants: Policy and practice.
Wellcome Open Research,
2, 15-15.
Abstract:
Returning genome sequences to research participants: Policy and practice
Despite advances in genomic science stimulating an explosion of literature around returning health-related findings, the possibility of returning entire genome sequences to individual research participants has not been widely considered. Through direct involvement in large-scale translational genomics studies, we have identified a number of logistical challenges that would need to be overcome prior to returning individual genome sequence data, including verifying that the data belong to the requestor and providing appropriate informatics support. In addition, we identify a number of ethico-legal issues that require careful consideration, including returning data to family members, mitigating against unintended consequences, and ensuring appropriate governance. Finally, recognising that there is an opportunity cost to addressing these issues, we make some specific pragmatic suggestions for studies that are considering whether to share individual genomic datasets with individual study participants. If data are shared, research should be undertaken into the personal, familial and societal impact of receiving individual genome sequence data.
Abstract.
Evers JMG, Laskowski RA, Bertolli M, Clayton-Smith J, Deshpande C, Eason J, Elmslie F, Flinter F, Gardiner C, Hurst JA, et al (2017). Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.
Hum Mol Genet,
26(3), 519-526.
Abstract:
Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.
Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.
Abstract.
Author URL.
2016
Middleton A, Morley KI, Bragin E, Firth HV, Hurles ME, Wright CF, Parker M (2016). Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research.
European Journal of Human Genetics,
24(1), 21-29.
Abstract:
Attitudes of nearly 7000 health professionals, genomic researchers and publics toward the return of incidental results from sequencing research
Genome-wide sequencing in a research setting has the potential to reveal health-related information of personal or clinical utility for the study participant. There is increasing pressure to return research findings to participants that may not be related to the project aims, particularly when these could be used to prevent disease. Such secondary, unsolicited or 'incidental findings' (IFs) may be discovered unintentionally when interpreting sequence data, or as the result of a deliberate opportunistic screen. This cross-sectional, web-based survey investigated attitudes of 6944 individuals from 75 countries towards returning IFs from genome research. Participants included four relevant stakeholder groups: 4961 members of the public, 533 genetic health professionals, 843 non-genetic health professionals and 607 genomic researchers who were invited via traditional media, social media and professional e-mail list-serve. Treatability and perceived utility of incidental results were deemed important with 98% of stakeholders personally interested in learning about preventable life-threatening conditions. Although there was a generic interest in receiving genomic information, stakeholders did not expect researchers to opportunistically screen for IFs in a research setting. On many items, genetic health professionals had significantly more conservative views compared with other stakeholders. This finding demonstrates a disconnect between the views of those handling the findings of research and those participating in research. Exploring, evaluating and ultimately addressing this disconnect should form a priority for researchers and clinicians alike. This social sciences study offers the largest dataset, published to date, of attitudes towards issues surrounding the return of IFs from sequencing research.
Abstract.
Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SHA, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, et al (2016). Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
Nature Genetics,
48(9), 1060-1065.
Abstract:
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (-2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
Abstract.
Laskowski RA, Tyagi N, Johnson D, Joss S, Kinning E, McWilliam C, Splitt M, Thornton JM, Firth HV, Wright CF, et al (2016). Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: Application to the WD40 domain.
Human Molecular Genetics,
25(5), 927-935.
Abstract:
Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: Application to the WD40 domain
We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six newde novo missense diagnoses in TBL1XR1 fromthe Deciphering Developmental Disorders study, together with population variation data, we show that the β-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the β-propeller, where 'hotspot' residues affect the binding of β-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease.
Abstract.
McRae JF, Clayton S, Fitzgerald TW, Kaplanis J, Prigmore E, Rajan D, Sifrim A, Aitken S, Akawi N, Alvi M, et al (2016). Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: the Deciphering Developmental Disorders Study.
Wright CF, Hurles ME, Firth HV (2016). Principle of proportionality in genomic data sharing. Nature Reviews Genetics, 17(1), 1-2.
2015
Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, et al (2015). Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.
Nat Genet,
47(11), 1363-1369.
Abstract:
Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.
Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.
Abstract.
Author URL.
Chatzimichali EA, Brent S, Hutton B, Perrett D, Wright CF, Bevan AP, Hurles ME, Firth HV, Swaminathan GJ (2015). Facilitating Collaboration in Rare Genetic Disorders Through Effective Matchmaking in DECIPHER.
Human Mutation,
36(10), 941-949.
Abstract:
Facilitating Collaboration in Rare Genetic Disorders Through Effective Matchmaking in DECIPHER
DECIPHER (https://decipher.sanger.ac.uk) is a web-based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well-phenotyped patients suffering from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy-number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype-phenotype characteristics. DECIPHER also provides mechanisms to encourage collaboration among a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer-reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ~250 registered centers on more than 51,500 patients (~18000 patients with consent for data sharing and ~25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource.
Abstract.
Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, Van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T, et al (2015). Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.
The Lancet,
385(9975), 1305-1314.
Abstract:
Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data
Background Human genome sequencing has transformed our understanding of genomic variation and its relevance to health and disease, and is now starting to enter clinical practice for the diagnosis of rare diseases. The question of whether and how some categories of genomic findings should be shared with individual research participants is currently a topic of international debate, and development of robust analytical workflows to identify and communicate clinically relevant variants is paramount. Methods the Deciphering Developmental Disorders (DDD) study has developed a UK-wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. After data analysis, pertinent genomic variants were returned to individual research participants via their local clinical genetics team. Findings Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation. Interpretation Implementation of a robust translational genomics workflow is achievable within a large-scale rare disease research study to allow feedback of potentially diagnostic findings to clinicians and research participants. Systematic recording of relevant clinical data, curation of a gene-phenotype knowledge base, and development of clinical decision support software are needed in addition to automated exclusion of almost all variants, which is crucial for scalable prioritisation and review of possible diagnostic variants. However, the resource requirements of development and maintenance of a clinical reporting system within a research setting are substantial. Funding Health Innovation Challenge Fund, a parallel funding partnership between the Wellcome Trust and the UK Department of Health.
Abstract.
Fitzgerald TW, Gerety SS, Jones WD, van Kogelenberg M, King DA, McRae J, Morley KI, Parthiban V, Al-Turki S, Ambridge K, et al (2015). Large-scale discovery of novel genetic causes of developmental disorders.
NATURE,
519(7542), 223-+.
Author URL.
Fitzgerald TW, Gerety SS, Jones WD, Van Kogelenberg M, King DA, McRae J, Morley KI, Parthiban V, Al-Turki S, Ambridge K, et al (2015). Large-scale discovery of novel genetic causes of developmental disorders.
Nature,
519(7542), 223-228.
Abstract:
Large-scale discovery of novel genetic causes of developmental disorders
Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.
Abstract.
Mircsof D, Langouët M, Rio M, Moutton S, Siquier-Pernet K, Bole-Feysot C, Cagnard N, Nitschke P, Gaspar L, Žnidarič M, et al (2015). Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects.
Nat Neurosci,
18(12), 1731-1736.
Abstract:
Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects.
The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.
Abstract.
Author URL.
Middleton A, Morley KI, Bragin E, Firth HV, Hurles ME, Wright CF, Parker M (2015). No expectation to share incidental findings in genomic research. The Lancet, 385(9975), 1289-1290.
Middleton A, Wright CF, Morley KI, Bragin E, Firth HV, Hurles ME, Parker M (2015). Potential research participants support the return of raw sequence data.
Journal of Medical Genetics,
52(8), 571-574.
Abstract:
Potential research participants support the return of raw sequence data
Health-related results that are discovered in the process of genomic research should only be returned to research participants after being clinically validated and then delivered and followed up within a health service. Returning such results may be difficult for genomic researchers who are limited by resources or unable to access appropriate clinicians. Raw sequence data could, in theory, be returned instead. This might appear nonsensical as, on its own, it is a meaningless code with no clinical value. Yet, as and when direct to consumer genomics services become more widely available (and can be endorsed by independent health professionals and genomic researchers alike), the return of such data could become a realistic proposition. We explore attitudes from
Abstract.
2014
Wright CF, Zimmern RL (2014). Conceptual issues for screening in the genomic era - time for an update?.
Epidemiology Biostatistics and Public Health,
11(4), 1-8.
Abstract:
Conceptual issues for screening in the genomic era - time for an update?
Background: Screening tests are ubiquitous in modern medicine; however a consensus view on the criteria that distinguish screening from clinical testing remains strangely elusive. although numerous definitions of screening have been suggested, there is considerable variation amongst them, leading to confusion and disagreement amongst clinicians and public health professionals alike. In light of developments in genomics, the question of what screening entails is becoming increasingly pressing.
Abstract.
Bragin E, Chatzimichali EA, Wright CF, Hurles ME, Firth HV, Bevan AP, Swaminathan GJ (2014). DECIPHER: Database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation.
Nucleic Acids Research,
42(D1).
Abstract:
DECIPHER: Database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation
The DECIPHER database (https://decipher.sanger.ac.uk/) is an accessible online repository of genetic variation with associated phenotypes that facilitates the identification and interpretation of pathogenic genetic variation in patients with rare disorders. Contributing to DECIPHER is an international consortium of >200 academic clinical centres of genetic medicine and 1600 clinical geneticists and diagnostic laboratory scientists. Information integrated from a variety of bioinformatics resources, coupled with visualization tools, provides a comprehensive set of tools to identify other patients with similar genotype-phenotype characteristics and highlights potentially pathogenic genes. In a significant development, we have extended DECIPHER from a database of just copy-number variants to allow upload, annotation and analysis of sequence variants such as single nucleotide variants (SNVs) and InDels. Other notable developments in DECIPHER include a purpose-built, customizable and interactive genome browser to aid combined visualization and interpretation of sequence and copy-number variation against informative datasets of pathogenic and population variation. We have also introduced several new features to our deposition and analysis interface. This article provides an update to the DECIPHER database, an earlier instance of which has been described elsewhere [Swaminathan et al. (2012) DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders. Hum. Mol. Genet. 21, R37-R44]. © 2013 the Author(s). Published by Oxford University Press.
Abstract.
Wright CF, Middleton A, Parker M (2014). Ethical, legal and social issues in clinical genomics. In (Ed)
Genomic Medicine Principles and Practice, Oxford University Press (UK).
Abstract:
Ethical, legal and social issues in clinical genomics
Abstract.
Köhler S, Doelken SC, Mungall CJ, Bauer S, Firth HV, Bailleul-Forestier I, Black GCM, Brown DL, Brudno M, Campbell J, et al (2014). The Human Phenotype Ontology project: Linking molecular biology and disease through phenotype data.
Nucleic Acids Research,
42(D1).
Abstract:
The Human Phenotype Ontology project: Linking molecular biology and disease through phenotype data
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. © 2013 the Author(s). Published by Oxford University Press.
Abstract.
2013
Middleton A, Parker M, Wright CF, Bragin E, Hurles ME (2013). Empirical research on the ethics of genomic research. American Journal of Medical Genetics, Part A, 161(8), 2099-2101.
Moorthie S, Hall A, Wright CF (2013). Informatics and clinical genome sequencing: Opening the black box.
Genetics in Medicine,
15(3), 165-171.
Abstract:
Informatics and clinical genome sequencing: Opening the black box
Adoption of whole-genome sequencing as a routine biomedical tool is dependent not only on the availability of new high-throughput sequencing technologies, but also on the concomitant development of methods and tools for data collection, analysis, and interpretation. It would also be enormously facilitated by the development of decision support systems for clinicians and consideration of how such information can best be incorporated into care pathways. Here we present an overview of the data analysis and interpretation pipeline, the wider informatics needs, and some of the relevant ethical and legal issues. Copyright © 2012, American College of Medical Genetics and Genomics.
Abstract.
Wright CF, Middleton A, Burton H, Cunningham F, Humphries SE, Hurst J, Birney E, Firth HV (2013). Policy challenges of clinical genome sequencing. BMJ (Online), 347
2012
Swaminathan GJ, Bragin E, Chatzimichali EA, Corpas M, Bevan AP, Wright CF, Carter NP, Hurles ME, Firth HV (2012). Decipher: Web-based, community resource for clinical interpretation of rare variants in developmental disorders.
Human Molecular Genetics,
21(R1).
Abstract:
Decipher: Web-based, community resource for clinical interpretation of rare variants in developmental disorders
Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome. © the Author 2012. Published by Oxford University Press. All rights reserved.
Abstract.
Wright C, MacArthur DG (2012). Direct-to-Consumer Genetic Testing. In (Ed)
Molecular Genetics and Personalized Medicine, Springer Science & Business Media.
Abstract:
Direct-to-Consumer Genetic Testing
Abstract.
Wright CF, Wei Y, Higgins JP, Sagoo GS (2012). Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis.
BMC Research Notes,
5Abstract:
Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis
Background: Cell-free fetal DNA (cffDNA) can be detected in maternal blood during pregnancy, opening the possibility of early non-invasive prenatal diagnosis for a variety of genetic conditions. Since 1997, many studies have examined the accuracy of prenatal fetal sex determination using cffDNA, particularly for pregnancies at risk of an X-linked condition. Here we report a review and meta-analysis of the published literature to evaluate the use of cffDNA for prenatal determination (diagnosis) of fetal sex. We applied a sensitive search of multiple bibliographic databases including PubMed (MEDLINE), EMBASE, the Cochrane library and Web of Science. Results: Ninety studies, incorporating 9,965 pregnancies and 10,587 fetal sex results met our inclusion criteria. Overall mean sensitivity was 96.6% (95% credible interval 95.2% to 97.7%) and mean specificity was 98.9% (95% CI = 98.1% to 99.4%). These results vary very little with trimester or week of testing, indicating that the performance of the test is reliably high. Conclusions: Based on this review and meta-analysis we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA. Using cffDNA in prenatal diagnosis to replace or complement existing invasive methods can remove or reduce the risk of miscarriage. Future work should concentrate on the economic and ethical considerations of implementing an early non-invasive test for fetal sex. © 2012 Wright et al.; licensee BioMed Central Ltd.
Abstract.
Dent THS, Wright CF, Stephan BCM, Brayne C, Janssens ACJW (2012). Risk prediction models: a framework for assessment.
Public Health Genomics,
15(2), 98-105.
Abstract:
Risk prediction models: a framework for assessment
Background: Medical risk prediction models estimate the likelihood of future health-related events. Many make use of information derived from analysis of the genome. Models predict health outcomes such as cardiovascular disease, stroke and cancer, and for some conditions several models exist. Although risk models can help decision-making in clinical medicine and public health, they can also be harmful, for example, by misdirecting clinical effort away from those who are most likely to benefit towards people with less need, thus exacerbating health inequalities. Discussion: Risk prediction models need careful assessment before implementation, but the current approach to their development, evaluation and implementation is inappropriate. As a result, some models are pressed into use before it is clear whether they are suitable, while in other cases there is confusion about which model to use. This paper proposes an approach to the appraisal of risk-scoring models, based on a conference of UK experts. Summary: By specifying what needs to be known before a model can be judged suitable for translation from research into practice, we can ensure that useful models are taken up promptly, that less well-proven ones undergo further evaluation and that resources are not wasted on ineffective ones. © 2011 S. Karger AG, Basel.
Abstract.
Middleton A, Parker M, Bragin E, Wright CF, Morley K, Bevan AP, Firth H, Hurles M (2012). Sharing genomic research data: launch of an international ethics study.
Author URL.
2011
Wright CF, Hall A, Zimmern RL (2011). Regulating direct-to-consumer genetic tests: What is all the fuss about?.
Genetics in Medicine,
13(4), 295-300.
Abstract:
Regulating direct-to-consumer genetic tests: What is all the fuss about?
The number of genetic tests available direct-to-consumer has burgeoned over the last few years, prompting numerous calls for tighter regulation of these services. However, there is a lack of consensus about the most appropriate and achievable level of regulation, particularly given the global nature of the market. By consideration of potential for direct and indirect harms caused by genetic susceptibility or genomic profiling tests, in this study we offer an overarching framework that we believe to be feasible for the regulation of direct-to-consumer genetic tests and likely to be relevant to other forms of predictive testing. We suggest that just five key requirements would adequately protect the consumer: a proportionate set of consent procedures; formal laboratory accreditation; evidence of a valid gene-disease association; appropriately qualified staff to interpret the test result; and consumer protection legislation to prevent false or misleading claims. © 2011 Lippincott Williams & Wilkins.
Abstract.
Moorthie S, Mattocks CJ, Wright CF (2011). Review of massively parallel DNA sequencing technologies.
HUGO Journal,
5(1-4), 1-12.
Abstract:
Review of massively parallel DNA sequencing technologies
Since the development of technologies that can determine the base-pair sequence of DNA, the ability to sequence genes has contributed much to science and medicine. However, it has remained a relatively costly and laborious process, hindering its use as a routine biomedical tool. Recent times are seeing rapid developments in this field, both in the availability of novel sequencing platforms, as well as supporting technologies involved in processes such as targeting and data analysis. This is leading to significant reductions in the cost of sequencing a human genome and the potential for its use as a routine biomedical tool. This review is a snapshot of this rapidly moving field examining the current state of the art, forthcoming developments and some of the issues still to be resolved prior to the use of new sequencing technologies in routine clinical diagnosis. © 2011 Springer Science+Business Media B.V.
Abstract.
Janssens ACJW, Ioannidis JPA, Bedrosian S, Boffetta P, Dolan SM, Dowling N, Fortier I, Freedman AN, Grimshaw JM, Gulcher J, et al (2011). Strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS): Explanation and elaboration. Journal of Clinical Epidemiology, 64(8).
Janssens ACJW, Ioannidis JPA, Bedrosian S, Boffetta P, Dolan SM, Dowling N, Fortier I, Freedman AN, Grimshaw JM, Gulcher J, et al (2011). Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration.
European Journal of Clinical Investigation,
41(9), 1010-1035.
Abstract:
Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. © 2011 the Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.
Abstract.
Janssens ACJW, Ioannidis JPA, Bedrosian S, Boffetta P, Dolan SM, Dowling N, Fortier I, Freedman AN, Grimshaw JM, Gulcher J, et al (2011). Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration.
European Journal of Epidemiology,
26(4), 313-337.
Abstract:
Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration
The rapid and continuing progress in gene discovery for complex diseases is fuelling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by prior reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. © the Author(s) 2011.
Abstract.
Janssens ACJW, Ioannidis JPA, Bedrosian S, Boffetta P, Dolan SM, Dowling N, Fortier I, Freedman AN, Grimshaw JM, Gulcher J, et al (2011). Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration.
European Journal of Human Genetics,
19(5).
Abstract:
Strengthening the reporting of genetic risk prediction studies (GRIPS): Explanation and elaboration
The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis. © 2011 Macmillan Publishers Limited.
Abstract.
(2011). Strengthening the reporting of genetic risk prediction studies: the GRIPS statement. Journal of Clinical Epidemiology, 64(8), 843-847.
Firth HV, Wright CF (2011). The Deciphering Developmental Disorders (DDD) study. Developmental Medicine and Child Neurology, 53(8), 702-703.
2010
Wright CF, Kroese M (2010). Evaluation of genetic tests for susceptibility to common complex diseases: Why, when and how?.
Human Genetics,
127(2), 125-134.
Abstract:
Evaluation of genetic tests for susceptibility to common complex diseases: Why, when and how?
Recent research into the human genome has generated a wealth of scientific knowledge and increased both public and professional interest in the concept of personalised medicine. Somewhat unexpectedly, in addition to increasing our understanding about the genetic basis for numerous diseases, these new discoveries have also spawned a burgeoning new industry of 'consumer genetic testing'. In this paper, we present the principles learnt though the evaluation of tests for single gene disorders and suggest a comparable framework for the evaluation of genetic tests for susceptibility to common complex diseases. Both physicians and the general public will need to be able to assess the claims made by providers of genetic testing services, and ultimately policy-makers will need to decide if and when such tests should be offered through state funded healthcare systems. © 2009 Springer-Verlag.
Abstract.
Burke W, Burton H, Hall AE, Karmali M, Khoury MJ, Knoppers B, Meslin EM, Stanley F, Wright CF, Zimmern RL, et al (2010). Extending the reach of public health genomics: What should be the agenda for public health in an era of genome-based and "personalized" medicine?.
Genetics in Medicine,
12(12), 785-791.
Abstract:
Extending the reach of public health genomics: What should be the agenda for public health in an era of genome-based and "personalized" medicine?
The decade following the completion of the Human Genome Project has been marked by divergent claims about the utility of genomics for improving population health. On the one hand, genomics is viewed as the harbinger of a brave new world in which novel treatments rectify known causes of disease. On the other hand, genomics may have little practical relevance to the principal causes or remedies of diseases which are predominantly social or environmental in origin, particularly in low- and middle-income countries. Those supportive of a role for public health genomics argue that increasing knowledge of genomics and molecular pathology could unlock effective diagnostic techniques and treatments, and better target public health interventions. To resolve some of these tensions, an international multidisciplinary meeting was held in May 2010 in Ickworth, United Kingdom, with the aim of setting an agenda for the development of public health in an era of genome-based and " personalized" medicine. A number of key themes emerged, suggesting a need to reconfigure both the focus for existing genomic research and the stage at which funding is targeted, so that priority is given to areas of greatest potential health impact and that translation from basic science to implementation is given greater emphasis. To support these developments, there should be an immediate, sustained and systematic effort to provide an evidence base. These deliberations formed the basis for six key recommendations, which could guide the practice of public health in an era of genomics and personalized medicine. © 2010 Lippincott Williams & Wilkins.
Abstract.
Hall A, Bostanci A, Wright CF (2010). Non-invasive prenatal diagnosis using cell-free fetal DNA technology: Applications and implications.
Public Health Genomics,
13(4), 246-255.
Abstract:
Non-invasive prenatal diagnosis using cell-free fetal DNA technology: Applications and implications
Cell-free fetal DNA and RNA circulating in maternal blood can be used for the early non-invasive prenatal diagnosis (NIPD) of an increasing number of genetic conditions, both for pregnancy management and to aid reproductive decision-making. Here we present a brief review of the scientific and clinical status of the technology, and an overview of key ethical, legal and social issues raised by the analysis of cell-free fetal DNA for NIPD. We suggest that the less invasive nature of the technology brings some distinctive issues into focus, such as the possibility of broader uptake of prenatal diagnosis and access to the technology directly by the consumer via the internet, which have not been emphasised in previous work in this area. We also revisit significant issues that are familiar from previous debates about prenatal testing. Since the technology seems to transect existing distinctions between screening and diagnostic tests, there are important implications for the form and process involved in obtaining informed consent or choice. This analysis forms part of the work undertaken by a multidisciplinary group of experts which made recommendations about the implementation of this technology within the UK National Health Service. Copyright © 2010 S. Karger AG, Basel.
Abstract.
Wright CF, Zimmern RL (2010). Quality issues in the evaluation and regulation of genetic testing services: a public health approach. In (Ed)
Quality Issues in Clinical Genetic Services, 267-275.
Abstract:
Quality issues in the evaluation and regulation of genetic testing services: a public health approach
Abstract.
Wright CF, Brice P, Stewart A, Burton H (2010). Realising the benefits of genetics for health. The Lancet, 376(9750), 1370-1371.
Wright CF, Gregory-Jones S (2010). Size of the direct-to-consumer genomic testing market.
Genetics in Medicine,
12(9).
Abstract:
Size of the direct-to-consumer genomic testing market
There has been enormous interest in the recent development of consumer genomics services, but very little is known about their impact. Using publicly available information, we estimate that the market for genetic susceptibility tests for complex diseases is much smaller than previously suggested, and hence consider that regulation through restrictive statutory legislation may be excessive. Copyright © American College of Medical Genetics.
Abstract.
2009
Burton H, Wright CF, Zimmern R (2009). A new strategic phase for genomic medicine in UK health services. Genome Medicine, 1(10), 93-93.
Wright CF, Hall A, Matthews FE, Brayne C (2009). Biomarkers, Dementia, and Public Health. Annals of the New York Academy of Sciences, 1180(1), 11-19.
Wright CF, Chitty LS (2009). Cell-free fetal DNA and RNA in maternal blood: implications for safer antenatal testing. BMJ, 339(jul06 2), b2451-b2451.
Dent THS, Wright CF (2009). RISK PREDICTION IN CORONARY HEART DISEASE AND OTHER CONDITIONS: CURRENT UNCERTAINTIES AND FUTURE OPPORTUNITIES.
Author URL.
2008
Wright CF, Burton H (2008). The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis. Human Reproduction Update, 15(1), 139-151.
2005
Wright CF, Teichmann SA, Clarke J, Dobson CM (2005). The importance of sequence diversity in the aggregation and evolution of proteins. Nature, 438(7069), 878-881.
2004
Wright CF, Christodoulou J, Dobson CM, Clarke J (2004). The importance of loop length in the folding of an immunoglobulin domain.
PROTEIN ENGINEERING DESIGN & SELECTION,
17(5), 443-453.
Author URL.
Wright CF, Christodoulou J, Dobson CM, Clarke J (2004). The importance of loop length in the folding of an immunoglobulin domain. Protein Engineering Design and Selection, 17(5), 443-453.
Wright CF, Steward A, Clarke J (2004). Thermodynamic Characterisation of Two Transition States Along Parallel Protein Folding Pathways. Journal of Molecular Biology, 338(3), 445-451.
2003
Wright CF, Lindorff-Larsen K, Randles LG, Clarke J (2003). Parallel protein-unfolding pathways revealed and mapped. Nature Structural & Molecular Biology, 10(8), 658-662.