Journal articles
De Franco E, Wakeling M, Frew R, Russ-Silsby J, Peters C, Marks S, Hattersley A, Flanagan S (In Press). A biallelic loss-of-function PDIA6 variant in a second patient with polycystic kidney disease, infancy-onset diabetes, and microcephaly. Clinical Genetics
Wakeling M, Owens NDL, Hopkinson JR, Johnson MB, Houghton JAL, Dastamani A, Flaxman CS, Wyatt RC, Hewat TI, Hopkins JJ, et al (In Press). A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1.
Nature GeneticsAbstract:
A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1
Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory. element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell ‘disallowed’ gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.
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Demirbilek H, Cayir A, Flanagan S, Yıldırım R, Kor Y, Gurbuz F, Haliloğlu B, Yıldız M, Baran RT, Akbas ED, et al (In Press). Clinical characteristics and long-term follow-up of patients with diabetes due to PTF1A enhancer mutations. Journal of Clinical Endocrinology and Metabolism
De Franco E, Wakeling M, Flanagan S, Hattersley A (In Press). Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP. EMBO Molecular Medicine
De Franco E, Flanagan S, Johnson M (In Press). Neonatal and early onset diabetes in Ukraine: atypical features and mortality. Diabetic Medicine
De Franco E, Owens N, Hattersley A, Flanagan S, Wakeling M, Johnson M, Wright C (In Press). Primate-specific ZNF808 is essential for pancreatic development in humans. Nature Genetics
Johnson M, Patel K, De Franco E, McDonald T, Hudson M, Dobbs R, Ellard S, Flanagan S, Hattersley A, Oram R, et al (In Press). Type 1 Diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta-cells. Diabetologia
Wyatt RC, Olek S, De Franco E, Samans B, Patel K, Houghton J, Walter S, Schulze J, Bacchetta R, Hattersley AT, et al (2023). FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome.
J Clin Immunol,
43(3), 662-669.
Abstract:
FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome.
Pathogenic FOXP3 variants cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a progressive autoimmune disease resulting from disruption of the regulatory T cell (Treg) compartment. Assigning pathogenicity to novel variants in FOXP3 is challenging due to the heterogeneous phenotype and variable immunological abnormalities. The number of cells with demethylation at the Treg cell-specific demethylated region (TSDR) is an independent biomarker of IPEX. We aimed to investigate if diagnosing IPEX at presentation with isolated diabetes could allow for effective monitoring of disease progression and assess whether TSDR analysis can aid FOXP3 variant classification and predict disease course. We describe a large genetically diagnosed IPEX cohort (n = 65) and 13 individuals with other monogenic autoimmunity subtypes in whom we quantified the proportion of cells with FOXP3 TSDR demethylation, normalized to the number with CD4 demethylation (%TSDR/CD4) and compare them to 29 unaffected controls. IPEX patients presenting with isolated diabetes (50/65, 77%) often later developed enteropathy (20/50, 40%) with a median interval of 23.5 weeks. %TSDR/CD4 was a good discriminator of IPEX vs. unaffected controls (ROC-AUC 0.81, median 13.6% vs. 8.5%, p
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Aly HH, De Franco E, Flanagan SE, Elhenawy YI (2023). MNX1 mutations causing neonatal diabetes: Review of the literature and report of a case with extra-pancreatic congenital defects presenting in severe diabetic ketoacidosis.
J Diabetes Investig,
14(4), 516-521.
Abstract:
MNX1 mutations causing neonatal diabetes: Review of the literature and report of a case with extra-pancreatic congenital defects presenting in severe diabetic ketoacidosis.
The MNX1 gene encodes a homeobox transcription factor found to be important for pancreatic beta cell differentiation and development. Mutations of the MNX1 gene that cause permanent neonatal diabetes mellitus (PNDM) are rare and have been reported in only two cases. Both cases presented with hyperglycemia, with one case having isolated PNDM while the other had PNDM and multiple neurologic, skeletal, lung, and urologic congenital anomalies resulting in death in early infancy. We describe the genetic and clinical features of a preterm male infant with a homozygous [c.816C > A p.(Phe272Leu)] MNX1 mutation. Our proband is the first case to present in severe diabetic ketoacidosis (DKA), indicating severe insulin deficiency. Unlike the previously reported female case who had the same mutation and presented with isolated PNDM, our proband had hypospadias and congenital umbilical hernia and showed poor growth on follow up. Our case suggests that MNX1 mutations causing NDM can result in a range of extra-pancreatic features and a variable phenotype, similar to other transcription factors causing NDM such as GATA6 and GATA4 mutations. We also cannot exclude the possibility of sex-biased expression of MNX1 gene (which was recently reported for other monogenic/neonatal diabetes genes such as the NEUROD1 and HNF4A in humans) since the two male cases had associated multiple anomalies while the female case had isolated PNDM. Our report further defines the phenotype caused by recessive homozygous MNX1 mutations and explores potential new mechanisms regulating MNX1 gene expression which should be further explored.
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Hughes AE, De Franco E, Freathy RM, Fetal Insulin and Growth Consortium, Flanagan SE, Hattersley AT (2023). Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth.
J Clin Invest,
133(6).
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Amaratunga SA, Hussein Tayeb T, Muhamad Sediq RN, Hama Salih FK, Dusatkova P, Wakeling MN, De Franco E, Pruhova S, Lebl J (2023). Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq.
DiabetologiaAbstract:
Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq
Abstract
. Aims/hypothesis
. Monogenic diabetes is estimated to account for 1–6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity.
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. Methods
. Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing.
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. Results
. A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes.
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. Conclusions/interpretation
. This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
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. Graphical Abstract
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Tobias DK, Merino J, Ahmad A, Aiken C, Benham JL, Bodhini D, Clark AL, Colclough K, Corcoy R, Cromer SJ, et al (2023). Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine. Nature Medicine, 29(10), 2438-2457.
Russ-Silsby J, Patel KA, Laver TW, Hawkes G, Johnson MB, Wakeling MN, Patil PP, Hattersley AT, Flanagan SE, Weedon MN, et al (2023). The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus.
Diabetes,
72(11), 1729-1734.
Abstract:
The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus.
ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human β-cell function.
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Murphy R, Colclough K, Pollin TI, Ikle JM, Svalastoga P, Maloney KA, Saint-Martin C, Molnes J, ADA/EASD PMDI, Misra S, et al (2023). The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.
Commun Med (Lond),
3(1).
Abstract:
The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion.
BACKGROUND: Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field. METHODS: Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice. RESULTS: There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted. CONCLUSIONS: We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.
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Abdelmeguid Y, Mowafy EW, Marzouk I, Franco ED, ElSayed S (2022). Clinical and molecular characteristics of infantile-onset diabetes mellitus in Egypt.
Ann Pediatr Endocrinol Metab,
27(3), 214-222.
Abstract:
Clinical and molecular characteristics of infantile-onset diabetes mellitus in Egypt.
PURPOSE: in patients diagnosed with diabetes mellitus (DM) before the age of 12 months, there is an increasing recognition of diabetes caused by single-gene mutations, also known as monogenic diabetes of infancy or neonatal DM (NDM). This study aimed to classify patients at Alexandria University Children's Hospital (AUCH) diagnosed with infantile-onset DM into type 1 DM (T1DM) or NDM and to detect differences in molecular characteristics of NDM patients at our center in comparison to other countries. METHODS: This retrospective/prospective observational study was conducted on 39 patients diagnosed with infantile-onset DM (age of onset ≤1 year) at AUCH from January 2003 to November 2020. The patients were divided into 2 groups according to age at the onset of DM: ≤6 months and >6-12 months. Molecular testing was done in patients diagnosed with DM at ≤6 months and those with negative autoantibodies. RESULTS: Twelve patients were diagnosed with DM at age ≤6 months and 27 patients were diagnosed between 6-12 months. Seventeen patients (43.6%) had T1DM, whereas 9 patients (23.1%) had genetically confirmed NDM, including 3 harboring novel mutations. The most common genetic causes of NDM were EIF2AK3 mutations (n=3), followed by KCNJ11 (n=2) and ABCC8 (n=2). Other mutations included SLC19A2 (n=1) and INS (n=1). Three patients with potassium ATP channel mutations were transferred from insulin to sulfonylurea treatment. CONCLUSION: it is essential to identify patients with NDM clinically and confirm the diagnosis by molecular testing to distinguish them from T1DM as it helps in refining their management, predicting prognosis, and guiding genetic counseling.
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Wyatt RC, Hagopian WA, Roep BO, Patel KA, Resnick B, Dobbs R, Hudson M, EXE-T1D Consortium, De Franco E, Ellard S, et al (2022). Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes.
Diabetologia,
65(7), 1179-1184.
Abstract:
Congenital beta cell defects are not associated with markers of islet autoimmunity, even in the context of high genetic risk for type 1 diabetes.
AIMS/HYPOTHESIS: a key unanswered question in type 1 diabetes is whether beta cells initiate their own destruction or are victims of an aberrant immune response (beta cell suicide or homicide?). To investigate this, we assessed islet autoantibodies in individuals with congenital beta cell defects causing neonatal diabetes mellitus (NDM). METHODS: We measured autoantibodies to GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) in 242 individuals with NDM (median age diagnosed 1.8 months [IQR 0.39-2.9 months]; median age collected 4.6 months [IQR 1.8-27.6 months]; median diabetes duration 2 months [IQR 0.6-23 months]), including 75 whose NDM resulted from severe beta cell endoplasmic reticulum (ER) stress. As a control cohort we also tested samples from 69 diabetes-free individuals (median age collected 9.9 months [IQR 9.0-48.6 months]) for autoantibodies. RESULTS: We found low prevalence of islet autoantibodies in individuals with monogenic NDM; 13/242 (5.4% [95% CI 2.9, 9.0%]) had detectable GADA, IA-2A and/or ZnT8A. This was similar to the proportion in the control participants who did not have diabetes (1/69 positive [1.4%, 95% CI 0.03, 7.8%], p=0.3). Importantly, monogenic individuals with beta cell ER stress had a similar rate of GADA/IA-2A/ZnT8A positivity to non-ER stress aetiologies (2.7% [95% CI 0.3, 9.3%] vs 6.6% [95% CI 3.3, 11.5%] p=0.4). We observed no association between islet autoimmunity and genetic risk, age at testing (including 30 individuals >10 years at testing) or diabetes duration (p>0.4 for all). CONCLUSIONS/INTERPRETATION: Our data support the hypothesis that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells.
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Mackay D, Bliek J, Kagami M, Tenorio-Castano J, Pereda A, Brioude F, Netchine I, Papingi D, de Franco E, Lever M, et al (2022). First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.
Clin Epigenetics,
14(1).
Abstract:
First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.
BACKGROUND: Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses. RESULTS: We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories. CONCLUSIONS: Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
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Ngoc CTB, Dung VC, De Franco E, Lan NN, Thao BP, Khanh NN, Flanagan SE, Craig ME, Hoang NH, Dien TM, et al (2022). Genetic Etiology of Neonatal Diabetes Mellitus in Vietnamese Infants and Characteristics of Those with INS Gene Mutations. Frontiers in Endocrinology, 13
Globa E, Zelinska N, Lebl J, De Franco E, Colclough K (2022). Genetická různorodost monogenního diabetu na Ukrajině. Česko-Slovenská Pediatrie, 77(4), 214-214.
Pachapure SS, Badiger S, Tadakanahalli S, De Franco E, Manthale A, Kulkarni V (2022). Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome caused by GLIS3 mutation: a case report and review of literature. Journal of Pediatric Endocrinology and Diabetes, 2(2), 86-89.
Laver TW, De Franco E, Johnson MB, Patel KA, Ellard S, Weedon MN, Flanagan SE, Wakeling MN (2022). SavvyCNV: Genome-wide CNV calling from off-target reads.
PLOS Computational Biology,
18(3), e1009940-e1009940.
Abstract:
SavvyCNV: Genome-wide CNV calling from off-target reads
Identifying copy number variants (CNVs) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions. We have developed a new tool, SavvyCNV, to exploit this ‘free data’ to call CNVs across the genome. We benchmarked SavvyCNV against five state-of-the-art CNV callers using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming the five other tools at calling CNVs genome-wide, using off-target or on-target reads from targeted panel and exome sequencing. We then applied SavvyCNV to clinical samples sequenced using a targeted panel and were able to call previously undetected clinically-relevant CNVs, highlighting the utility of this tool within the diagnostic setting. SavvyCNV outperforms existing tools for calling CNVs from off-target reads. It can call CNVs genome-wide from targeted panel and exome data, increasing the utility and diagnostic yield of these tests. SavvyCNV is freely available at https://github.com/rdemolgen/SavvySuite.
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Polla DL, Edmondson AC, Duvet S, March ME, Sousa AB, Lehman A, CAUSES Study, Niyazov D, van Dijk F, Demirdas S, et al (2021). Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation.
Am J Hum Genet,
108(7), 1342-1349.
Abstract:
Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation.
EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.
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Splittstoesser V, Vollbach H, Plamper M, Garbe W, De Franco E, Houghton JAL, Dueker G, Ganschow R, Gohlke B, Schreiner F, et al (2021). Case Report: Extended Clinical Spectrum of the Neonatal Diabetes with Congenital Hypothyroidism Syndrome.
Front Endocrinol (Lausanne),
12Abstract:
Case Report: Extended Clinical Spectrum of the Neonatal Diabetes with Congenital Hypothyroidism Syndrome.
BACKGROUND: Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability. CASE PRESENTATION: We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis. CONCLUSIONS: Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.
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London S, De Franco E, Elias-Assad G, Barhoum MN, Felszer C, Paniakov M, Weiner SA, Tenenbaum-Rakover Y (2021). Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins.
Front Endocrinol (Lausanne),
12Abstract:
Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins.
BACKGROUND: Mutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys. CASES: We describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up. CONCLUSIONS: This report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.
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Laimon W, El-Ziny M, El-Hawary A, Elsharkawy A, Salem NA-B, Aboelenin HM, Awad MH, Flanagan SE, De Franco E (2021). Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience. Acta Diabetologica, 58(12), 1689-1700.
Denkboy Öngen Y, Eren E, Demirbaş Ö, Sobu E, Ellard S, De Franco E, Tarım Ö (2021). Genotype and Phenotype Heterogeneity in Neonatal Diabetes: a Single Centre Experience in Turkey.
J Clin Res Pediatr Endocrinol,
13(1), 80-87.
Abstract:
Genotype and Phenotype Heterogeneity in Neonatal Diabetes: a Single Centre Experience in Turkey.
OBJECTIVE: Neonatal diabetes mellitus (NDM) may be transient or permanent, and the majority is caused by genetic mutations. Early diagnosis is essential to select the patients who will respond to oral treatment. In this investigation, we aimed to present the phenotype and genotype of our patients with NDM and share our experience in a single tertiary center METHODS: a total of 16 NDM patients from 12 unrelated families are included in the study. The clinical presentation, age at diagnosis, perinatal and family history, consanguinity, gender, hemoglobin A1c, C-peptide, insulin, insulin autoantibodies, genetic mutations, and response to treatment are retrospectively evaluated. RESULTS: the median age at diagnosis of diabetes was five months (4 days-18 months) although six patients with a confirmed genetic diagnosis were diagnosed >6 months. Three patients had KCNJ11 mutations, six had ABCC8 mutations, three had EIF2AK3 mutations, and one had a de novo INS mutation. All the permanent NDM patients with KCNJ11 and ABCC8 mutations were started on sulfonylurea treatment resulting in a significant increase in C-peptide level, better glycemic control, and discontinuation of insulin. CONCLUSION: Although NDM is defined as diabetes diagnosed during the first six months of life, and a diagnosis of type 1 diabetes is more common between the ages of 6 and 24 months, in rare cases NDM may present as late as 12 or even 24 months of age. Molecular diagnosis in NDM is important for planning treatment and predicting prognosis. Therefore, genetic testing is essential in these patients.
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Hughes AE, De Franco E, Globa E, Zelinska N, Hilgard D, Sifianou P, Hattersley AT, Flanagan SE (2021). Identification of GCK-maturity-onset diabetes of the young in cases of neonatal hyperglycemia: a case series and review of clinical features.
Pediatr Diabetes,
22(6), 876-881.
Abstract:
Identification of GCK-maturity-onset diabetes of the young in cases of neonatal hyperglycemia: a case series and review of clinical features.
Heterozygous mutations in GCK result in a persistent, mildly raised glucose from birth, but it is usually diagnosed in adulthood as maturity-onset diabetes of the young (MODY), where hyperglycemia is often an incidental finding. The hyperglycemia of GCK-MODY is benign and does not require treatment, but is important to be aware of, particularly in females where it has implications for managing pregnancy. We present three cases of neonatal hyperglycemia resulting from a heterozygous mutation in GCK, illustrating its clinical presentation and evolution in early life. In summary, as with adults, neonatal hyperglycemia is an incidental finding, does not require treatment and has no adverse consequences for health. Neonates and their parents should be referred for genetic testing to confirm the diagnosis, avoid a label of diabetes and enable pregnancy counseling for females found to be affected.
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Støy J, De Franco E, Ye H, Park S-Y, Bell GI, Hattersley AT (2021). In celebration of a century with insulin - Update of insulin gene mutations in diabetes.
Mol Metab,
52Abstract:
In celebration of a century with insulin - Update of insulin gene mutations in diabetes.
BACKGROUND: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years, it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights into both the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can be found in patients with diabetes diagnosed outside the first year of life. SCOPE OF REVIEW: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes. MAJOR CONCLUSIONS: the dominant mutations in the INS gene typically affect the secondary structure of the insulin protein, usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast, recessive INS gene mutations typically result in no functional protein being produced due to reduced insulin biosynthesis or loss-of-function mutations in the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and within patients with identical mutations.
Abstract.
Author URL.
Bowman P, Mathews F, Barbetti F, Shepherd MH, Sanchez J, Piccini B, Beltrand J, Letourneau-Freiberg LR, Polak M, Greeley SAW, et al (2021). Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients with Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes.
Diabetes Care,
44(1), 35-42.
Abstract:
Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients with Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes.
OBJECTIVE: ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM. RESEARCH DESIGN AND METHODS: We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K. Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods. RESULTS: Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%). CONCLUSIONS: Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.
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Author URL.
Can TBN, Tran MD, De Franco E, Ellard S, Houghton JAL, Nguyen NL, Bui PT, Nguyen NK, Flanagan SE, Craig ME, et al (2021). Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of K<sub>ATP</sub>-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.
FRONTIERS IN ENDOCRINOLOGY,
12 Author URL.
Ibrahim MN, Laghari TM, Riaz M, Khoso Z, Khan YN, Yasir M, Hanif MI, Flanagan SE, De Franco E, Raza J, et al (2021). Monogenic diabetes in Pakistani infants and children: challenges in a resource poor country.
J Pediatr Endocrinol Metab,
34(9), 1095-1103.
Abstract:
Monogenic diabetes in Pakistani infants and children: challenges in a resource poor country.
OBJECTIVES: to review the data of infants and children with suspected monogenic diabetes who underwent genetic testing. METHODS: Monogenic diabetes is a rare form of diabetes resulting from mutations in a single gene. It can be caused by dominant as well as recessive modes of inheritance. In a country like Pakistan where interfamily marriages are common the incidence of genetic disorders is increased. As Pakistan a resource-poor country, the diagnosis of insulin-dependent diabetes is often delayed and a genetic diagnosis of monogenic diabetes is extremely difficult. Children with clinical diagnosis of monogenic and syndromic diabates were recruited and blood samples were sent for genetic analysis. RESULTS: One thousand sixty four new cases diagnosed with type 1 diabetes were registered at the National Institute of Child Health, Karachi, in the last 10 years. of these 39 patients were selected for genetic testing who were diagnosed with diabetes/had a sibling diagnosed with diabetes before the age of nine months (n = 27) or had extra pancreatic features ( n= 12). We identified mutations in 18/27 cases diagnosed with diabetes before nine months of age. The most common genetic subtype was WolcottRallison syndrome caused by EIF2AK3 mutations (seven cases). KCNJ11 mutations were identified in two cases, ABCC8mutations were identified in four cases from three families, GCK and INS mutations were each identified in two cases, and one SLC2A2 mutation was identified in one case. A genetic diagnosis was made in 12/12 children from six families with diabetes diagnosed after the age of nine months who had extrapancreatic features. Six patients had genetically confirmed Wolfram syndrome (WFS1), three had thiamine-responsive megaloblastic anemia (SLC19A2) and three were diagnosed with histocytosis lymphadenopathy plus syndrome (SLC29A3). CONCLUSIONS: Genetic testing is essential to confirm a diagnosis of monogenic diabetes which guides clinical management and future counselling. Our study highlights the importance of diagnosing monogenic diabetes in the largely consanguineously-married population of Pakistan.
Abstract.
Author URL.
De Franco E (2021). Neonatal diabetes caused by disrupted pancreatic and β-cell development. Diabetic Medicine
I A, MA M, E DF, V G, S F, J G-H, G M, P R, L P, S E, et al (2021). Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.
Akerman I, Maestro MA, De Franco E, Grau V, Flanagan S, García-Hurtado J, Mittler G, Ravassard P, Piemonti L, Ellard S, et al (2021). Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.
Cell Rep,
35(2).
Abstract:
Neonatal diabetes mutations disrupt a chromatin pioneering function that activates the human insulin gene.
Despite the central role of chromosomal context in gene transcription, human noncoding DNA variants are generally studied outside of their genomic location. This limits our understanding of disease-causing regulatory variants. INS promoter mutations cause recessive neonatal diabetes. We show that all INS promoter point mutations in 60 patients disrupt a CC dinucleotide, whereas none affect other elements important for episomal promoter function. To model CC mutations, we humanized an ∼3.1-kb region of the mouse Ins2 gene. This recapitulated developmental chromatin states and cell-specific transcription. A CC mutant allele, however, abrogated active chromatin formation during pancreas development. A search for transcription factors acting through this element revealed that another neonatal diabetes gene product, GLIS3, has a pioneer-like ability to derepress INS chromatin, which is hampered by the CC mutation. Our in vivo analysis, therefore, connects two human genetic defects in an essential mechanism for developmental activation of the INS gene.
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Author URL.
Shrestha N, De Franco E, Arvan P, Cnop M (2021). Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence.
Front Endocrinol (Lausanne),
12Abstract:
Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence.
The notion that in diabetes pancreatic β-cells express endoplasmic reticulum (ER) stress markers indicative of increased unfolded protein response (UPR) signaling is no longer in doubt. However, what remains controversial is whether this increase in ER stress response actually contributes importantly to the β-cell failure of type 2 diabetes (akin to 'terminal UPR'), or whether it represents a coping mechanism that represents the best attempt of β-cells to adapt to changes in metabolic demands as presented by disease progression. Here an intercontinental group of experts review evidence for the role of ER stress in monogenic and type 2 diabetes in an attempt to reconcile these disparate views. Current evidence implies that pancreatic β-cells require a regulated UPR for their development, function and survival, as well as to maintain cellular homeostasis in response to protein misfolding stress. Prolonged ER stress signaling, however, can be detrimental to β-cells, highlighting the importance of "optimal" UPR for ER homeostasis, β-cell function and survival.
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Author URL.
Giannopoulou EZ, Ovcarov O, De Franco E, Kassberger F, Nusser S, Otto MC, Denzer C, Wabitsch M (2021). Transient neonatal diabetes due to a disease causing novel variant in the ATP-binding cassette subfamily C member 8 (ABCC8) gene unmasks maturity-onset diabetes of the young (MODY) diabetes cases within a family.
J Pediatr Endocrinol Metab,
34(2), 273-276.
Abstract:
Transient neonatal diabetes due to a disease causing novel variant in the ATP-binding cassette subfamily C member 8 (ABCC8) gene unmasks maturity-onset diabetes of the young (MODY) diabetes cases within a family.
OBJECTIVES: Neonatal diabetes mellitus (NDM) is a rare monogenic diabetes form, occurring mainly from ATP-binding cassette subfamily C member 8 (ABCC8) and KCNJ11 mutations. ABCC8 mutations have also been found to cause adult-onset diabetes. What is new?: •Novel ABCC8 mutation in an NDM case •Heterogeneous clinical presentation of diabetes and response to sulfonylurea therapy among family members with the same ABCC8 mutation. CASE PRESENTATION: We report the case of a newborn with NDM and a heterozygous ABCC8 novel variant (c.3835G>A), successfully treated with sulfonylurea. The same ABCC8 variant was found in two other family members, already treated for type 2 diabetes. CONCLUSIONS: This case demonstrates the variable phenotypic presentation of diabetes due to a novel ABCC8 mutation (c.3835G>A), ranging from transient NDM to adult-onset, insulin-demanding diabetes, among family members. Genetic testing in young individuals with a strong family history of diabetes, presenting with non-autoimmune diabetes is recommended as it can determine prognosis and treatment of affected family members.
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Author URL.
Kishore S, De Franco E, Cardenas-Diaz FL, Letourneau-Freiberg LR, Sanyoura M, Osorio-Quintero C, French DL, Greeley SAW, Hattersley AT, Gadue P, et al (2020). A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line.
Cell Stem Cell,
27(1), 137-146.e6.
Abstract:
A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line.
GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation. Screening the regulatory regions of the GATA6 gene in these patient cells and 32 additional agenesis patients revealed a higher minor allele frequency of a SNP 3' of the GATA6 coding sequence. Introduction of this minor allele SNP by genome editing confirmed its functionality in depressing GATA6 expression and the efficiency of pancreas differentiation. This work highlights a possible genetic modifier contributing to pancreatic agenesis and demonstrates the usefulness of using patient-induced pluripotent stem cells for targeted discovery and validation of non-coding gene variants affecting gene expression and disease penetrance.
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Author URL.
Oakley-Hannibal E, Ghali N, Pope FM, De Franco E, Ellard S, van Dijk FS, Brady AF (2020). A neuromuscular disorder with homozygosity for PIEZO2 gene variants: an important differential diagnosis for kyphoscoliotic Ehlers-Danlos Syndrome.
Clin Dysmorphol,
29(1), 69-72.
Author URL.
Abali ZY, De Franco E, Karakilic Ozturan E, Poyrazoglu S, Bundak R, Bas F, Flanagan SE, Darendeliler F (2020). Clinical Characteristics, Molecular Features, and Long-Term Follow-Up of 15 Patients with Neonatal Diabetes: a Single-Centre Experience.
Horm Res Paediatr,
93(7-8), 423-432.
Abstract:
Clinical Characteristics, Molecular Features, and Long-Term Follow-Up of 15 Patients with Neonatal Diabetes: a Single-Centre Experience.
BACKGROUND: Diabetes diagnosed within the first 6 months of life is defined as neonatal diabetes mellitus (NDM). Mutations in the KCNJ11, ABCC8, and INS genes are the most common cause of permanent NDM. In populations with a high rate of consanguinity, Wolcott-Rallison syndrome caused by biallelic EIF2AK3 mutations is common. METHODS: We studied the clinical characteristics and underlying genetic cause of disease in 15 individuals with diabetes onset before 6 months of age as defined by sustained hyperglycaemia requiring insulin treatment. Patients who had a remission of the diabetes, defined by a normal blood glucose and HbA1c value without insulin or sulphonylurea (SU) treatment, within the first 18 months of life were classified as having transient NDM (TNDM). RESULTS: We report 15 patients with NDM from 14 unrelated families, including 10 with reported parental consanguinity. 1/15 patients had a remission of diabetes, leading to a diagnosis of TNDM. Mutations were detected in 80% (n = 12/15) of the cohort (ABCC8 [n = 4], PTF1A-distal enhancer [n = 3], KCNJ11 [n = 2], EIF2AK3 [n = 1], INS [n = 1], and SLC19A2 [n = 1]). All cases were initially treated with multiple dose insulin injections. One patient with an ABCC8 mutation transitioned from insulin to SU resulting in improved metabolic control at the age of 20 years. CONCLUSION: Although the number of individuals born to consanguineous parents was considerably high in this cohort, KATP channel mutations (ABCC8/KCNJ11) were more common than EIF2AK3 mutations (n = 6 vs. n = 1). Genetic analyses should be performed in all NDM cases due to the potential impact on treatment and prognosis.
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Author URL.
De Franco E, Caswell R, Johnson MB, Wakeling MN, Zung A, Dũng VC, Bích Ngọc CT, Goonetilleke R, Vivanco Jury M, El-Khateeb M, et al (2020). De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
Diabetes,
69(3), 477-483.
Abstract:
De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1's fundamental role within this pathway.
Abstract.
Author URL.
E DF, R C, MB J, MN W, a Z, VC D, CT BN, R G, M VJ, M E-K, et al (2020). De novo mutations in EIF2B1 affecting eif2 signaling cause neonatal/early-onset diabetes and transient hepatic dysfunction.
De Franco E (2020). From Biology to Genes and Back Again: Gene Discovery for Monogenic Forms of Beta-Cell Dysfunction in Diabetes.
J Mol Biol,
432(5), 1535-1550.
Abstract:
From Biology to Genes and Back Again: Gene Discovery for Monogenic Forms of Beta-Cell Dysfunction in Diabetes.
This review focuses on gene discovery strategies used to identify monogenic forms of diabetes caused by reduced pancreatic beta-cell number (due to destruction or defective development) or impaired beta-cell function. Gene discovery efforts in monogenic diabetes have identified 36 genes so far. These genetic causes have been identified using four main approaches: linkage analysis, candidate gene sequencing and most recently, exome and genome sequencing. The advent of next-generation sequencing has allowed researchers to move away from linkage analysis (relying on large pedigrees and/or multiple families with the same genetic condition) and candidate gene (relying on previous knowledge on the gene's role) strategies to use a gene agnostic approach, utilizing genetic evidence (such as variant frequency, predicted variant effect on protein function, and predicted mode of inheritance) to identify the causative mutation. This approach led to the identification of seven novel genetic causes of monogenic diabetes, six by exome sequencing and one by genome sequencing. In many of these cases, the disease-causing gene was not known to be important for beta-cell function prior to the gene discovery study. These novel findings highlight a new role for gene discovery studies in furthering our understanding of beta-cell function and dysfunction in diabetes. While many gene discovery studies in the past were led by knowledge in the field (through the candidate gene strategy), now they often lead the scientific advances in the field by identifying new important biological players to be further characterized by in vitro and in vivo studies.
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Author URL.
Li R, Reichert SC, a Turner S, van Jaarsveld RH, Massink MPG, van den Boogaard M-JH, Del Toro M, Rodríguez-Palmero A, Fourcade S, Schlüter A, et al (2020). HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.
Clin Genet,
98(1), 91-98.
Abstract:
HNRNPH1-related syndromic intellectual disability: Seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome.
Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.
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Author URL.
Uroic AS, Milenkovic D, De Franco E, Bilic E, Putarek NR, Krnic N (2020). Importance of Immediate Thiamine Therapy in Children with Suspected Thiamine-Responsive Megaloblastic Anemia—Report on Two Patients Carrying a Novel SLC19A2 Gene Mutation. Journal of Pediatric Genetics, 11(03), 236-239.
Novak A, Bowman P, Kraljevic I, Tripolski M, Houghton JAL, De Franco E, Shepherd MH, Skrabic V, Patel KA (2020). Transient Neonatal Diabetes: an Etiologic Clue for the Adult Diabetologist.
Can J Diabetes,
44(2), 128-130.
Author URL.
De Franco E, Saint‐Martin C, Brusgaard K, Knight Johnson AE, Aguilar‐Bryan L, Bowman P, Arnoux J, Larsen AR, Sanyoura M, Greeley SAW, et al (2020). Update of variants identified in the pancreatic β‐cell K. <sub>ATP</sub>. channel genes. <i>KCNJ11</i>. and. <i>ABCC8</i>. in individuals with congenital hyperinsulinism and diabetes. Human Mutation, 41(5), 884-905.
De Franco E, Lytrivi M, Ibrahim H, Montaser H, Wakeling M, Fantuzzi F, Patel K, Demarez C, Cai Y, Igoillo-Esteve M, et al (2020). YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. Journal of Clinical Investigation, 130
De Franco E, Watson RA, Weninger WJ, Wong CC, Flanagan SE, Caswell R, Green A, Tudor C, Lelliott CJ, Geyer SH, et al (2019). A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.
American Journal of Human Genetics,
104(5), 985-989.
Abstract:
A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development
We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.
Abstract.
Rautengarten C, Quarrell OW, Stals K, Caswell RC, De Franco E, Baple E, Burgess N, Jokhi R, Heazlewood JL, Offiah AC, et al (2019). A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia.
Hum Mol Genet,
28(21), 3543-3551.
Abstract:
A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia.
We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a 'Schneckenbecken-like dysplasia.' the effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum.
Abstract.
Author URL.
E DF, RA W, WJ W, CC W, SE F, R C, a G, C T, CJ L, SH G, et al (2019). A specific CNOT1 mutation results in a novel syndrome of pancreatic agenesis and holoprosencephaly through impaired pancreatic and neurological development.
Mann N, Kause F, Henze EK, Gharpure A, Shril S, Connaughton DM, Nakayama M, Klämbt V, Majmundar AJ, Wu C-HW, et al (2019). CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.
Am J Hum Genet,
105(6), 1286-1293.
Abstract:
CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.
Abstract.
Author URL.
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.
Madani H, Elkaffas R, Alkholy B, Musa N, Shaalan Y, Elkaffas R, Hassan M, Hafez M, Flanagan SE, De Franco E, et al (2019). Identification of novel variants in neonatal diabetes mellitus genes in Egyptian patients with permanent NDM.
International Journal of Diabetes in Developing Countries,
39(1), 53-59.
Abstract:
Identification of novel variants in neonatal diabetes mellitus genes in Egyptian patients with permanent NDM
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes resulting from mutations in more than 20 different genes encoding proteins playing a key role in the normal function of the pancreatic beta-cell. Mutations in the genes encoding the ATP-sensitive potassium channel, ABCC8, and KCNJ11 and insulin (INS) gene are the most common causes of NDM; however, in consanguineous populations, EIF2AK3 mutations are more common. Identification of the causative mutations by genetic testing is critical for appropriate management and to guide genetic counseling. To determine the genetic etiology of NDM in diabetic neonates and infants diagnosed before the age of 1 year and to describe their phenotype/genotype characteristics, DNA sequencing of coding regions and intronic boundaries of ABCC8, KCNJ11, INS, and EIF2AK3 genes was undertaken in 20 patients. Further, targeted next-generation sequencing was performed for other genes known to cause NDM. ABCC8 mutations were found in two patients (10%), with compound heterozygous mutations (p.N131 K/p.R598*) in one patient and a homozygous mutation (p.R1554Q) in the another patient. Heterozygous p.A174G and p.V59M mutations of KCNJ11 were identified in two patients (10%), and homozygous EIF2AK3 mutations were identified in two further patients (p.T905fs and p.R653T) (10%). No INS mutations were identified. Further testing identified a SLC19A2 mutation (p.W387*) in one patient (5%) and the same homozygous GCK mutation in two siblings (p.A188T). ABCC8, KCNJ11, and EIF2AK3 mutations were the main genetic causes of permanent NDM among Egyptian neonates.
Abstract.
Annamalai AK, Ellard S, Shanmugam M, Jai Juganya TP, De Franco E (2019). Juvenile diabetes and visual impairment: Wolfram syndrome.
QJM,
112(10), 803-804.
Author URL.
De Franco E, Molecular Genetics UOEMS (2019). Next-generation Sequencing in the Identification of New Genes Causing Beta-cell Dysfunction. US Endocrinology, 15(1).
Lundgren M, De Franco E, Arnell H, Fischler B (2019). Practical management in Wolcott-Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: a case report.
Clin Case Rep,
7(6), 1133-1138.
Abstract:
Practical management in Wolcott-Rallison syndrome with associated hypothyroidism, neutropenia, and recurrent liver failure: a case report.
Wolcott-Rallison syndrome is a rare genetic syndrome of neonatal diabetes, liver failure, and growth retardation. We present a case with a EIF2AK3 p.(Arg902Ter) mutation, additionally complicated by hypothyroidism, impaired renal function, and exocrine pancreas insufficiency, focusing on clinical management. For its optimization, thorough care of multiple organ systems is needed.
Abstract.
Author URL.
Laver TW, De Franco E, Johnson MB, Patel K, Ellard S, Weedon MN, Flanagan SE, Wakeling MN (2019). SavvyCNV: genome-wide CNV calling from off-target reads.
Abstract:
SavvyCNV: genome-wide CNV calling from off-target reads
AbstractIdentifying copy number variants (CNVS) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data to call CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions - SavvyCNV exploits this ‘free data’.We benchmarked SavvyCNV using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming five state-of-the-art CNV callers at calling CNVs genome-wide using off-target or on-target reads from targeted panel and exome sequencing. Furthermore SavvyCNV was able to call previously undetected clinically-relevant CNVs from targeted panel data highlighting the utility of this tool within the diagnostic setting. SavvyCNV is freely available.
Abstract.
Johnson MB, De Franco E, Greeley SAW, Letourneau LR, Gillespie KM, International DS-PNDM Consortium, Wakeling MN, Ellard S, Flanagan SE, Patel KA, et al (2019). Trisomy 21 is a Cause of Permanent Neonatal Diabetes That is Autoimmune but Not HLA Associated.
Diabetes,
68(7), 1528-1535.
Abstract:
Trisomy 21 is a Cause of Permanent Neonatal Diabetes That is Autoimmune but Not HLA Associated.
Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis
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Asl SN, Vakili R, Vakili S, Soheilipour F, Hashemipour M, Ghahramani S, De Franco E, Yaghootkar H (2019). Wolcott-Rallison syndrome in Iran: a common cause of neonatal diabetes.
J Pediatr Endocrinol Metab,
32(6), 607-613.
Abstract:
Wolcott-Rallison syndrome in Iran: a common cause of neonatal diabetes.
Background Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by neonatal/early-onset non-autoimmune insulin-dependent diabetes, multiple epiphyseal dysphasia and growth retardation. It is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3). We aimed to study the clinical characteristics and frequency of the disease in the Iranian population. Methods We recruited 42 patients who referred to the endocrine and metabolism clinic at Mashhad Imam Reza Hospital with neonatal diabetes. Molecular screening of KCNJ11, INS, ABCC8 and EIF2AK3 was performed at the Exeter Molecular Genetics Laboratory, UK. We calculated the frequency of the disease in 124 patients referred from Iran to the Exeter Molecular Genetics Laboratory for genetic screening and compared it to other countries worldwide. Results We identified seven patients as having Wolcott-Rallison syndrome. Genetic testing confirmed the clinical diagnosis and indicated five novel mutations. Only two patients developed clinical features of the syndrome by 6 months of age. of all 124 cases of Iranian neonatal diabetes referred to the Exeter Molecular Genetics Laboratory for genetic screening, 28 patients (22.58%) had a recessive mutation in EIF2AK3. Conclusions the results of this study raises awareness of the condition and provides further accurate data on the genetic and clinical presentation of Wolcott-Rallison syndrome in the Iranian population. Our study highlights the importance of genetic testing in patients from consanguineous families with diabetes diagnosed within the first 6 months of life.
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Gole E, Oikonomou S, Ellard S, De Franco E, Karavanaki K (2018). A Novel KCNJ11 Mutation Associated with Transient Neonatal Diabetes.
J Clin Res Pediatr Endocrinol,
10(2), 175-178.
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A Novel KCNJ11 Mutation Associated with Transient Neonatal Diabetes.
Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes that presents in the first 6 months of life. Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the ATP-sensitive potassium (KATP ) channel can lead to transient NDM (TNDM) or to permanent NDM (PNDM). A female infant presented on the 22nd day of life with severe hyperglycemia and ketoacidosis (glucose: 907mg/dL, blood gas pH: 6.84, HCO3: 6 mmol/L). She was initially managed with intravenous (IV) fluids and IV insulin. Ketoacidosis resolved within 48 hours and she was started on subcutaneous insulin injections with intermediate acting insulin NPH twice daily requiring initially 0.75-1.35 IU/kg/d. Pre-prandial C-peptide levels were 0.51 ng/mL (normal: 1.77-4.68). Insulin requirements were gradually reduced and insulin administration was discontinued at the age of 10 months with subsequent normal glucose and HbA1c levels. C-peptide levels normalized (pre-prandial: 1.6 ng/mL, postprandial: 2 ng/mL). Genetic analysis identified a novel missense mutation (p.Pro254Gln) in the KCNJ11 gene. We report a novel KCNJ11 mutation in a patient who presented in the first month of life with a phenotype of NDM that subsided at the age of 10 months. It is likely that the novel p.P254Q mutation results in mild impairment of the KATP channel function leading to TNDM.
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Johnson MBJ, Patel K, De Franco E, Houghton J, McDonald T, Ellard S, Flanagan S, Hattersley A (2018). A Type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early onset clustering of polygenic autoimmunity with diabetes. Diabetologia
Yildiz M, Akcay T, Aydin B, Akgun A, Dogan BB, De Franco E, Ellard S, Onal H (2018). Emergence of insulin resistance following empirical glibenclamide therapy: a case report of neonatal diabetes with a recessive INS gene mutation.
J Pediatr Endocrinol Metab,
31(3), 345-348.
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Emergence of insulin resistance following empirical glibenclamide therapy: a case report of neonatal diabetes with a recessive INS gene mutation.
BACKGROUND: As KATP channel mutations are the most common cause of neonatal diabetes mellitus (NDM) and patients with these mutations can be treated with oral sulfonylureas, empiric therapy is a common practice for NDM patients. CASE PRESENTATION: a non-syndromic, small for gestational age baby born to first-degree consanguineous parents was diagnosed with NDM. Because of hypo- and hyperglycemic episodes and variability in insulin requirement, we initiated a trial of glibenclamide, with a presumptive diagnosis of NDM caused by a KATP channel mutation. However, this empiric sulfonylurea trial did not improve the patient's glycemic control and resulted in resistance to exogenous insulin. Genetic testing identified a previously reported homozygous INS promoter mutation (c.-331C>G), which was not responsive to sulfonylurea therapy. CONCLUSIONS: in light of our results, we recommend to confirm the genetic diagnosis as soon as possible and decide on sulfonylurea treatment after a genetic diagnosis is confirmed.
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Al Senani A, Hamza N, Al Azkawi H, Al Kharusi M, Al Sukaiti N, Al Badi M, Al Yahyai M, Johnson M, De Franco E, Flanagan S, et al (2018). Genetic mutations associated with neonatal diabetes mellitus in Omani patients.
J Pediatr Endocrinol Metab,
31(2), 195-204.
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Genetic mutations associated with neonatal diabetes mellitus in Omani patients.
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare disorder worldwide where diabetes is diagnosed in the first 6 months of life. However, Oman has a relatively high incidence of NDM. METHODS: in this study, we investigated the genetic etiologies underlying NDM and their prevalence in Oman. We collected a cohort of 24 NDM patients, with and without genetic diagnosis, referred to our center from 2007 to 2015. All patients without a genetic diagnosis were tested for mutations in 23 NDM-associated genes using a custom-targeted next-generation sequencing (NGS) panel and methylation analysis of the 6q24 locus. RESULTS: a genetic abnormality was detected in 15/24 (62.5%) of our Omani NDM patients. We report the detection of 6q24 methylation abnormalities and KCNJ11 mutations for the first time in Omani NDM patients. Unlike Western populations where NDM is predominantly due to mutations in the KCNJ11, ABCC8 and INS genes, NDM due to homozygous GCK gene mutations were most prevalent in Oman, having been observed in seven out of 15 NDM patients in whom we established the genetic etiology. This reflects the high degree of consanguinity which makes recessive conditions more likely. CONCLUSIONS: the results of this study are likely to impact any future strategy to introduce genetic testing for NDM disorders within the national healthcare system in Oman.
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Savova R, De Franco E, Shaw-Smith C, Georgieva R, Konstantinova M, Archinkova M, Panteleeva E, Kaneva A, Marinov R, Ellard S, et al (2018). Marked intrafamilial variability of exocrine and endocrine pancreatic phenotypes due to a splice site mutation in GATA6.
Biotechnology and Biotechnological Equipment,
32(1), 124-129.
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Marked intrafamilial variability of exocrine and endocrine pancreatic phenotypes due to a splice site mutation in GATA6
The objective of this study was to describe the clinical characteristics of syndromic neonatal diabetes in a family with a GATA6 mutation. A girl, currently aged 12 years 3 months, was born with intrauterine growth retardation: weight 1600 g (–4.3 SDS) at term. After birth, foramen ovale and patent ductus arteriosus (PDA) were diagnosed by echocardiography. Diabetes was diagnosed on the 9th day after birth. Exocrine pancreatic insufficiency was clinically diagnosed at about 2 years of age and pancreatic agenesis was revealed later by magnetic resonance imaging. Her father had undergone surgery during infancy for PDA and had developed insulin dependent diabetes at 12 years of age. Ultrasound revealed a thin pancreas with normal length and anatomical structure. He has subclinical exocrine pancreatic insufficiency, low insulin needs and no late complications of diabetes up to the age of 40 years. Sequencing of GATA6 identified a heterozygous splicing mutation, 1136-2A>G, in the girl and her father. Testing of the paternal grandparents showed that the mutation was likely to have arisen de novo in the father. Identification of a GATA6 mutation explains the cardiac anomalies and diabetes in this family. This case highlights the marked intra-familial variability of both exocrine and endocrine pancreatic phenotypes in patients with GATA6 mutations.
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Şıklar Z, de Franco E, Johnson MB, Flanagan SE, Ellard S, Ceylaner S, Boztuğ K, Doğu F, İkincioğulları A, Kuloğlu Z, et al (2018). Monogenic Diabetes Not Caused By Mutations in Mody Genes: a Very Heterogenous Group of Diabetes.
Exp Clin Endocrinol Diabetes,
126(10), 612-618.
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Monogenic Diabetes Not Caused By Mutations in Mody Genes: a Very Heterogenous Group of Diabetes.
Monogenic diabetes represents a heterogeneous group of disorders resulting from a single gene defect leading to disruption of insulin secretion or a reduction in the number of beta cells. Despite the classification of monogenic diabetes into neonatal diabetes or maturity onset diabetes of the young (MODY) according to age of onset, not every case can be classified into those 2 groups. We evaluated patients with monogenic diabetes diagnosed during the last 10 year period. Type 1 DM, MODY, and patients with negative autoantibodies and no mutation in a known gene were excluded from the study. Thirteen patients were diagnosed with monogenic diabetes in Department of Pediatric Endocrinology, Ankara University School of Medicine, Ankara, Turkey. Five of them were diagnosed after 6 months of age. Five had a KATP channel defect. Mutations in genes resulting in destruction of beta cells were detected in 7 patients, with 4 cases having a WFS, 2 an LRBA, and one a IL2RA mutation. Additional systemic findings were seen in 6/13 patients, with 5/6 having severe immune system dysfunction. Treatment with sulphonylurea was successful in two patients. The other patients were given insulin in differing doses. Four patients died during follow-up, three of which had immune system dysfunction. Monogenic diabetes can be diagnosed after 6 months of age, even with positive autoantibodies. Immune dysfunction was a common feature in our cohort and should be investigated in all patients with early-onset monogenic diabetes. Mortality of patients with monogenic diabetes and additional autoimmunity was high in our cohort and is likely to reflect the multisystem nature of these diseases.
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Evliyaoğlu O, Ercan O, Ataoğlu E, Zübarioğlu Ü, Özcabı B, Dağdeviren A, Erdoğan H, De Franco E, Ellard S (2018). Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation.
J Clin Res Pediatr Endocrinol,
10(2), 168-174.
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Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation.
Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients’ fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.
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Demirbilek H, Hatipoglu N, Gul U, Tatli ZU, Ellard S, Flanagan SE, De Franco E, Kurtoglu S (2018). Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1.
Pediatr Diabetes,
19(5), 898-904.
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Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1.
The basic helix-loop-helix (bHLH) transcription factor, neuronal differentiation 1 (NEUROD1) (also known as BETA2) is involved in the development of neural elements and endocrine pancreas. Less than 10 reports of adult-onset non-insulin-dependent diabetes mellitus (NIDDM) due to heterozygous NEUROD1 mutations and 2 cases with permanent neonatal diabetes mellitus (PNDM) and neurological abnormalities due to homozygous NEUROD1 mutations have been published. A 13 year-old female was referred to endocrine department due to hyperglycemia. She was on insulin therapy following a diagnosis of neonatal diabetes mellitus (NDM) at the age of 9-weeks but missed regular follow-up. Parents are second cousin. There was a significant family history of adult onset NIDDM including patient's father. Auxological measurements were within normal ranges. On laboratory examination blood glucose was 33.2 mmol/L with undetectable c-peptide and glycosylated hemoglobin level of 8.9% (73.8 mmol/mol). She had developed difficulty in walking at the age of 4 years which had worsened over time. On further evaluation, a diagnosis of visual impairment, mental retardation, ataxic gait, retinitis pigmentosa and sensory-neural deafness were considered. Cranial magnetic resonance imaging revealed cerebellar hypoplasia. Molecular genetic analysis using targeted next generation sequencing detected a novel homozygous missense mutation, p.Ile150Asn(c.449T>A), in NEUROD1. Both parents and 2 unaffected siblings were heterozygous for the mutation. We report the third case of PNDM with neurological abnormalities caused by homozygous NEUROD1 mutation, the first caused by a missense mutation. Heterozygous carriers of the p.Ile150Asn mutation were either unaffected or diagnosed with diabetes in adulthood. It is currently unclear whether the NEUROD1 heterozygous mutation has contributed to diabetes development in these individuals.
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Misra S, Vedovato N, Cliff E, De Franco E, Hattersley AT, Ashcroft FM, Oliver NS (2018). Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment.
Diabet MedAbstract:
Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment.
BACKGROUND: Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high-dose sulfonylureas. Complete transfer to sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements. CASE: a 22-year-old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin-pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose-titration with C-peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C-peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose-titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once-daily long-acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. CONCLUSION: in people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy. This article is protected by copyright. All rights reserved.
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Habeb AM, Flanagan SE, Zulali MA, Abdullah MA, Pomahačová R, Boyadzhiev V, Colindres LE, Godoy GV, Vasanthi T, Al Saif R, et al (2018). Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.
Diabetologia,
61(5), 1027-1036.
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Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.
AIMS/HYPOTHESIS: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes. METHODS: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire. RESULTS: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day. CONCLUSIONS/INTERPRETATION: in TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent. DATA AVAILABILITY: SLC19A2 mutation details have been deposited in the Decipher database ( https://decipher.sanger.ac.uk/ ).
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Flanagan SE, Dũng VC, Houghton JAL, De Franco E, Ngoc CTB, Damhuis A, Ashcroft FM, Harries LW, Ellard S (2017). An ABCC8 Nonsense Mutation Causing Neonatal Diabetes Through Altered Transcript Expression.
J Clin Res Pediatr Endocrinol,
9(3), 260-264.
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An ABCC8 Nonsense Mutation Causing Neonatal Diabetes Through Altered Transcript Expression.
The pancreatic ATP-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes, whilst loss-of-function mutations in these genes result in congenital hyperinsulinism. We report two patients with neonatal diabetes in whom we unexpectedly identified recessively inherited loss-of-function mutations. The aim of this study was to investigate how a homozygous nonsense mutation in ABCC8 could result in neonatal diabetes. The ABCC8 p.Glu747. was identified in two unrelated Vietnamese patients. This mutation is located within the in-frame exon 17 and RNA studies confirmed (a) the absence of full length SUR1 mRNA and (b) the presence of the alternatively spliced transcript lacking exon 17. Successful transfer of both patients to sulphonylurea treatment suggests that the altered transcript expression enhances the sensitivity of the K-ATP channel to Mg-ADP/ATP. This is the first report of an ABCC8 nonsense mutation causing a gain-of-channel function and these findings extend the spectrum of K-ATP channel mutations observed in patients with neonatal diabetes.
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De Franco E, Caswell R, Houghton JAL, Iotova V, Hattersley AT, Ellard S (2017). Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes.
Diabet Med,
34(4), 582-585.
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Analysis of cell-free fetal DNA for non-invasive prenatal diagnosis in a family with neonatal diabetes.
AIMS: an early genetic diagnosis of neonatal diabetes guides clinical management and results in improved treatment in ~ 40% of patients. In the offspring of individuals with neonatal diabetes, a prenatal diagnosis allows accurate estimation of the risk of developing diabetes and, eventually, the most appropriate treatment for the baby. In this study, we performed non-invasive prenatal genetic testing for a fetus at risk of inheriting a paternal KCNJ11 p.R201C mutation causing permanent neonatal diabetes. METHODS: a droplet digital polymerase chain reaction assay was used to detect the presence of the mutation in cell-free circulating DNA (cfDNA) extracted from maternal plasma at 12 and 16 weeks' gestation. RESULTS: the mutation was not detected in the cfDNA samples, suggesting that the fetus had not inherited the KCNJ11 mutation. The fetal DNA fraction was estimated at 6.2% and 10.7%, which is above the detection limit of the assay. The result was confirmed by Sanger sequencing after the baby's birth, confirming that the baby's risk of developing neonatal diabetes was reduced to that of the general population. CONCLUSIONS: We report the first case of non-invasive prenatal testing in a family with neonatal diabetes. A prenatal diagnosis in families at high risk of monogenic diabetes informs both prenatal and postnatal management. Although the clinical impact of this novel technology still needs to be assessed, its implementation in clinical practice (including cases at risk of inheriting mutations from the mother) will likely have a positive impact upon the clinical management of families affected by monogenic diabetes.
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Yau D, De Franco E, Flanagan SE, Ellard S, Blumenkrantz M, Mitchell JJ (2017). Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus.
Diagn Pathol,
12(1).
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Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus.
BACKGROUND: Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism. CASE PRESENTATION: the proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency noted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent congenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis were repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated due to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus also demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities. Despite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to have multiple cardiac abnormalities, requiring procedural intervention. Given the proband's spectrum of congenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous c.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in inclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated decay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while the father and remaining sibling were negative. The mother, who is healthy with no evidence of diabetes or cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation sequencing. CONCLUSION: We highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental mosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic variability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be strongly considered in cases of diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family members should be tested regardless of phenotype.
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Jain V, Satapathy A, Yadav J, Sharma R, Radha V, Mohan V, De Franco E, Ellard S (2017). Clinical and Molecular Characterization of Children with Neonatal Diabetes Mellitus at a Tertiary Care Center in Northern India.
Indian Pediatr,
54(6), 467-471.
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Clinical and Molecular Characterization of Children with Neonatal Diabetes Mellitus at a Tertiary Care Center in Northern India.
OBJECTIVE: to study the genetic mutations and clinical profile in children with neonatal diabetes mellitus. METHODS: Genetic evaluation, clinical management and follow-up of infants with neonatal diabetes. RESULTS: Eleven infants were studied of which eight had permanent neonatal diabetes. Median age at presentation was 8 weeks and mean (SD) birth weight was 2.4 (0.5) kg. Pathogenic genetic mutations were identified in 7 (63.6%) children; 3 infants with mutations in KCNJ11 gene and 1 in ABCC8 were switched to oral sulfonylureas; 2 infants had mutations in INS and 1 in ZFP57. CONCLUSION: Neonatal diabetes mellitus is a heterogeneous disorder. Identification of genetic cause guides clinical management.
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Reinauer C, Rosenbauer J, Bächle C, Herder C, Roden M, Ellard S, De Franco E, Karges B, Holl R, Enczmann J, et al (2017). Der klinische Verlauf beim frühmanifestem T1D ist unabhängig vom HLA DR-DQ Genotyp. Diabetologie und Stoffwechsel, 12(S 01), s1-s84.
De Franco E, Flanagan SE, Yagi T, Abreu D, Mahadevan J, Johnson MB, Jones G, Acosta F, Mulaudzi M, Lek N, et al (2017). Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.
Diabetes,
66(7), 2044-2053.
Abstract:
Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.
Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.
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Gabbay M, Ellard S, De Franco E, Moisés RS (2017). Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene.
J Clin Res Pediatr Endocrinol,
9(3), 274-277.
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Pancreatic Agenesis due to Compound Heterozygosity for a Novel Enhancer and Truncating Mutation in the PTF1A Gene.
Neonatal diabetes, defined as the onset of diabetes within the first six months of life, is very rarely caused by pancreatic agenesis. Homozygous truncating mutations in the PTF1A gene, which encodes a transcriptional factor, have been reported in patients with pancreatic and cerebellar agenesis, whilst mutations located in a distal pancreatic-specific enhancer cause isolated pancreatic agenesis. We report an infant, born to healthy non-consanguineous parents, with neonatal diabetes due to pancreatic agenesis. Initial genetic investigation included sequencing of KCNJ11, ABCC8 and INS genes, but no mutations were found. Following this, 22 neonatal diabetes associated genes were analyzed by a next generation sequencing assay. We found compound heterozygous mutations in the PTF1A gene: a frameshift mutation in exon 1 (c.437_462 del, p.Ala146Glyfs*116) and a mutation affecting a highly conserved nucleotide within the distal pancreatic enhancer (g.23508442A>G). Both mutations were confirmed by Sanger sequencing. Isolated pancreatic agenesis resulting from compound heterozygosity for truncating and enhancer mutations in the PTF1A gene has not been previously reported. This report broadens the spectrum of mutations causing pancreatic agenesis.
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Johnson MB, De Franco E, Lango Allen H, Al Senani A, Elbarbary N, Siklar Z, Berberoglu M, Imane Z, Haghighi A, Razavi Z, et al (2017). Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes.
Diabetes,
66(8), 2316-2322.
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Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes.
Young-onset autoimmune diabetes associated with additional autoimmunity usually reflects a polygenic predisposition, but rare cases result from monogenic autoimmunity. Diagnosing monogenic autoimmunity is crucial for patients' prognosis and clinical management. We sought to identify novel genetic causes of autoimmunity presenting with neonatal diabetes (NDM) (diagnosis
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Reinauer C, Rosenbauer J, Bächle C, Herder C, Roden M, Ellard S, De Franco E, Karges B, Holl RW, Enczmann J, et al (2017). The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes is Independent of the HLA DR-DQ Genotype.
Genes (Basel),
8(5).
Abstract:
The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes is Independent of the HLA DR-DQ Genotype.
INTRODUCTION: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored their influence on clinical and laboratory parameters. METHODS: Intermediate resolution HLA-DRB1, DQA1 and DQB1 typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years) and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis. RESULTS: Genetic variability was low, 44.6% (104/233) of early-onset T1D patients carried the highest-risk genotype HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01/DRB1*04-DQA1*03:01-DQB1*03:02 (HLA-DRB1*04 denoting 04:01/02/04/05), and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest (n = 83), moderate (n = 106) and low risk (n = 6) genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years), metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each p > 0.05). Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes. CONCLUSION: in this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation.
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Dimitri P, De Franco E, Habeb AM, Gurbuz F, Moussa K, Taha D, Wales JKH, Hogue J, Slavotinek A, Shetty A, et al (2016). An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).
Am J Med Genet A,
170(7), 1918-1923.
Abstract:
An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).
Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.
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Houghton JAL, Swift GH, Shaw-Smith C, Flanagan SE, de Franco E, Caswell R, Hussain K, Mohamed S, Abdulrasoul M, Hattersley AT, et al (2016). Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.
Diabetes,
65(9), 2810-2815.
Abstract:
Isolated Pancreatic Aplasia Due to a Hypomorphic PTF1A Mutation.
Homozygous truncating mutations in the helix-loop-helix transcription factor PTF1A are a rare cause of pancreatic and cerebellar agenesis. The correlation of Ptf1a dosage with pancreatic phenotype in a mouse model suggested the possibility of finding hypomorphic PTF1A mutations in patients with pancreatic agenesis or neonatal diabetes but no cerebellar phenotype. Genome-wide single nucleotide polymorphism typing in two siblings with neonatal diabetes from a consanguineous pedigree revealed a large shared homozygous region (31 Mb) spanning PTF1A Sanger sequencing of PTF1A identified a novel missense mutation, p.P191T. Testing of 259 additional patients using a targeted next-generation sequencing assay for 23 neonatal diabetes genes detected one additional proband and an affected sibling with the same homozygous mutation. All four patients were diagnosed with diabetes at birth and were treated with insulin. Two of the four patients had exocrine pancreatic insufficiency requiring replacement therapy but none of the affected individuals had neurodevelopmental delay. Transient transfection assays of the mutant protein demonstrated a 75% reduction in transactivation activity. This study shows that the functional severity of a homozygous mutation impacts the severity of clinical features found in patients.
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Antosik K, Gnys P, De Franco E, Borowiec M, Mysliwiec M, Ellard S, Mlynarski W (2016). Single patient in GCK-MODY family successfully re-diagnosed into GCK-PNDM through targeted next-generation sequencing technology.
Acta Diabetol,
53(2), 337-338.
Author URL.
Patel KA, Oram RA, Flanagan SE, De Franco E, Colclough K, Shepherd M, Ellard S, Weedon MN, Hattersley AT (2016). Type 1 Diabetes Genetic Risk Score: a Novel Tool to Discriminate Monogenic and Type 1 Diabetes.
Diabetes,
65(7), 2094-2099.
Abstract:
Type 1 Diabetes Genetic Risk Score: a Novel Tool to Discriminate Monogenic and Type 1 Diabetes
Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of &gt;0.280 (&gt;50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS &lt;5th T1D centile, 50–75th T1D centile, and &gt;75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS &gt;50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D.
Abstract.
Dimitri P, Habeb AM, Gurbuz F, Millward A, Wallis S, Moussa K, Akcay T, Taha D, Hogue J, Slavotinek A, et al (2015). Expanding the Clinical Spectrum Associated with GLIS3 Mutations.
J Clin Endocrinol Metab,
100(10), E1362-E1369.
Abstract:
Expanding the Clinical Spectrum Associated with GLIS3 Mutations.
CONTEXT: GLIS3 (GLI-similar 3) is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with 5 C2H2-type zinc finger domains. The protein is expressed early in embryogenesis and plays a critical role as both a repressor and activator of transcription. Human GLIS3 mutations are extremely rare. OBJECTIVE: the purpose of this article was determine the phenotypic presentation of 12 patients with a variety of GLIS3 mutations. METHODS: GLIS3 gene mutations were sought by PCR amplification and sequence analysis of exons 1 to 11. Clinical information was provided by the referring clinicians and subsequently using a questionnaire circulated to gain further information. RESULTS: We report the first case of a patient with a compound heterozygous mutation in GLIS3 who did not present with congenital hypothyroidism. All patients presented with neonatal diabetes with a range of insulin sensitivities. Thyroid disease varied among patients. Hepatic and renal disease was common with liver dysfunction ranging from hepatitis to cirrhosis; cystic dysplasia was the most common renal manifestation. We describe new presenting features in patients with GLIS3 mutations, including craniosynostosis, hiatus hernia, atrial septal defect, splenic cyst, and choanal atresia and confirm further cases with sensorineural deafness and exocrine pancreatic insufficiency. CONCLUSION: We report new findings within the GLIS3 phenotype, further extending the spectrum of abnormalities associated with GLIS3 mutations and providing novel insights into the role of GLIS3 in human physiological development. All but 2 of the patients within our cohort are still alive, and we describe the first patient to live to adulthood with a GLIS3 mutation, suggesting that even patients with a severe GLIS3 phenotype may have a longer life expectancy than originally described.
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Author URL.
De Franco E, Ellard S (2015). Genome, Exome, and Targeted Next-Generation Sequencing in Neonatal Diabetes.
Pediatric Clinics of North America,
62(4), 1037-1053.
Abstract:
Genome, Exome, and Targeted Next-Generation Sequencing in Neonatal Diabetes
The use of targeted gene panels now allows the analysis of all the genes known to cause a disease in a single test. For neonatal diabetes, this has resulted in a paradigm shift with patients receiving a genetic diagnosis early and the genetic results guiding their clinical management. Exome and genome sequencing are powerful tools to identify novel genetic causes of known diseases. For neonatal diabetes, the use of these technologies has resulted in the identification of 2 novel disease genes (. GATA6 and STAT3) and a novel regulatory element of PTF1A, in which mutations cause pancreatic agenesis.
Abstract.
De Franco E, Ellard S (2015). Genome, Exome, and Targeted Next-Generation Sequencing in Neonatal Diabetes.
Pediatric Clinics of North AmericaAbstract:
Genome, Exome, and Targeted Next-Generation Sequencing in Neonatal Diabetes
The use of targeted gene panels now allows the analysis of all the genes known to cause a disease in a single test. For neonatal diabetes, this has resulted in a paradigm shift with patients receiving a genetic diagnosis early and the genetic results guiding their clinical management. Exome and genome sequencing are powerful tools to identify novel genetic causes of known diseases. For neonatal diabetes, the use of these technologies has resulted in the identification of 2 novel disease genes (GATA6 and STAT3) and a novel regulatory element of PTF1A, in which mutations cause pancreatic agenesis.
Abstract.
De Franco E, Flanagan SE, Houghton JAL, Lango Allen H, Mackay DJG, Temple IK, Ellard S, Hattersley AT (2015). The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.
Lancet,
386(9997), 957-963.
Abstract:
The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.
BACKGROUND: Traditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes. METHODS: in this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes. FINDINGS: Between January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p4 years; p
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Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, McDonald TJ, Rajala H, Ramelius A, Barton J, et al (2014). Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Nat Genet,
46(8), 812-814.
Abstract:
Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.
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Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, et al (2014). Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.
Cell Metab,
19(1), 146-154.
Abstract:
Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.
Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.
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Shaw-Smith C, De Franco E, Lango Allen H, Batlle M, Flanagan SE, Borowiec M, Taplin CE, van Alfen-van der Velden J, Cruz-Rojo J, Perez de Nanclares G, et al (2014). GATA4 mutations are a cause of neonatal and childhood-onset diabetes.
Diabetes,
63(8), 2888-2894.
Abstract:
GATA4 mutations are a cause of neonatal and childhood-onset diabetes.
The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.
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Ellard S, De Franco E (2014). Next-generation sequencing for the diagnosis of monogenic diabetes and discovery of novel aetiologies.
Frontiers in Diabetes,
23, 71-86.
Abstract:
Next-generation sequencing for the diagnosis of monogenic diabetes and discovery of novel aetiologies
Monogenic diabetes describes a genetically heterogeneous set of disorders which are caused by a mutation in a single gene. For both major subtypes, maturity-onset diabetes of the young and neonatal diabetes, making a genetic diagnosis is important for clinical management because the genetic subtype defines the treatment. Mutations in at least 26 genes have been identified through studies using genetic linkage, candidate gene sequencing and most recently, exome sequencing. With the advent of next-generation sequencing technology, it is now possible to do a single test to identify mutations in any of the known genes, either for the purposes of a clinical diagnostic test or as a pre-screen in the search for novel disease genes. Exome sequencing focuses on the proteincoding regions of the genome and has been applied in a small number of monogenic diabetes studies. It requires a strategy for selecting those patients likely to have a monogenic aetiology, defining the likely mode of inheritance and filtering variants to identify possible deleterious variants for further investigation. The identification through exome sequencing of GATA6 mutations as the most common cause of pancreatic agenesis is likely to be the first of many new discoveries enabled by exome or genome sequencing.
Abstract.
Raimondo A, Chakera AJ, Thomsen SK, Colclough K, Barrett A, De Franco E, Chatelas A, Demirbilek H, Akcay T, Alawneh H, et al (2014). Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
Hum Mol Genet,
23(24), 6432-6440.
Abstract:
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
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Weedon MN, Cebola I, Patch A-M, Flanagan SE, De Franco E, Caswell R, Rodríguez-Seguí SA, Shaw-Smith C, Cho CH-H, Allen HL, et al (2014). Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.
Nat Genet,
46(1), 61-64.
Abstract:
Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.
The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.
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Catli G, Abaci A, Flanagan SE, De Franco E, Ellard S, Hattersley A, Guleryuz H, Bober E (2013). A novel GATA6 mutation leading to congenital heart defects and permanent neonatal diabetes: a case report.
Diabetes and Metabolism,
39(4), 370-374.
Abstract:
A novel GATA6 mutation leading to congenital heart defects and permanent neonatal diabetes: a case report
Permanent neonatal diabetes mellitus is a rare condition mostly due to heterozygous mutations in the KCNJ11, ABCC8 and INS genes. Neonatal diabetes due to pancreatic agenesis is extremely rare. Mutations in PDX1, PTF1A, HNF1B, EIF2AK3, RFX6 and GATA6 genes have been shown to result in pancreatic agenesis or hypoplasia. This report describes a 40-day-old male infant diagnosed with permanent neonatal diabetes associated with atrial septal defect, pulmonary stenosis, patent ductus arteriosus and a novel de novo heterozygous missense mutation (p.N466S) in the GATA6 gene with no evidence of exocrine pancreas insufficiency. In addition to permanent neonatal diabetes, the patient had transient idiopathic neonatal cholestasis and hypoglycaemic episodes unrelated to insulin treatment, features that are rarely described in children with permanent neonatal diabetes. © 2013 Elsevier Masson SAS.
Abstract.
De Franco E, Shaw-Smith C, Flanagan SE, Edghill EL, Wolf J, Otte V, Ebinger F, Varthakavi P, Vasanthi T, Edvardsson S, et al (2013). Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency.
Diabet Med,
30(5), e197-e200.
Abstract:
Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency.
AIMS: Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency. METHODS: PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded. RESULTS: Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case. CONCLUSIONS: This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment.
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De Franco E, Shaw-Smith C, Flanagan SE, Shepherd MH, International NDM Consortium, Hattersley AT, Ellard S (2013). GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency.
Diabetes,
62(3), 993-997.
Abstract:
GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency.
We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency.
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Ellard S, Lango Allen H, De Franco E, Flanagan SE, Hysenaj G, Colclough K, Houghton JAL, Shepherd M, Hattersley AT, Weedon MN, et al (2013). Improved genetic testing for monogenic diabetes using targeted next-generation sequencing.
Diabetologia,
56(9), 1958-1963.
Abstract:
Improved genetic testing for monogenic diabetes using targeted next-generation sequencing
Aims/hypothesis: Current genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene for analysis according to the patient's phenotype. Next-generation sequencing enables the simultaneous analysis of multiple genes in a single test. Our aim was to develop a targeted next-generation sequencing assay to detect mutations in all known MODY and neonatal diabetes genes. Methods: We selected 29 genes in which mutations have been reported to cause neonatal diabetes, MODY, maternally inherited diabetes and deafness (MIDD) or familial partial lipodystrophy (FPLD). An exon-capture assay was designed to include coding regions and splice sites. A total of 114 patient samples were tested - 32 with known mutations and 82 previously tested for MODY (n = 33) or neonatal diabetes (n = 49) but in whom a mutation had not been found. Sequence data were analysed for the presence of base substitutions, small insertions or deletions (indels) and exonic deletions or duplications. Results: in the 32 positive controls we detected all previously identified variants (34 mutations and 36 polymorphisms), including 55 base substitutions, ten small insertions or deletions and five partial/whole gene deletions/duplications. Previously unidentified mutations were found in five patients with MODY (15%) and nine with neonatal diabetes (18%). Most of these patients (12/14) had mutations in genes that had not previously been tested. Conclusions/interpretation: Our novel targeted next-generation sequencing assay provides a highly sensitive method for simultaneous analysis of all monogenic diabetes genes. This single test can detect mutations previously identified by Sanger sequencing or multiplex ligation-dependent probe amplification dosage analysis. The increased number of genes tested led to a higher mutation detection rate. © 2013 the Author(s).
Abstract.
Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, International Pancreatic Agenesis Consortium, Ferrer J, Hattersley AT, Ellard S, et al (2011). GATA6 haploinsufficiency causes pancreatic agenesis in humans.
Nat Genet,
44(1), 20-22.
Abstract:
GATA6 haploinsufficiency causes pancreatic agenesis in humans.
Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.
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