Maturity-onset Diabetes Of The Young Genes Research Articles

MODY Probability Calculator Is Suitable for MODY Screening in China: A Population-based Study.

Selecting appropriate individuals for genetic testing is essential due to the optimal treatment for maturity-onset diabetes of the young (MODY). However, how to effectively screen for MODY in China remains unclear. To validate the performance of current screening strategies in selecting patients with MODY based on a nationwide type 2 diabetes cohort. A panel of 14 MODY genes was analyzed from 1911 type 2 diabetes patients who were ages 15 to 35 years. Variants were evaluated according to the American College of Medical Genetics and Genomics guidelines. Based on this cohort, we simulated the 2 most frequently used screening strategies, including the traditional MODY criteria and the MODY probability calculator (MPC), to assess their ability to select patients with MODY. From a total of 1911 participants, 42 participants harbored pathogenic/likely pathogenic variants. The performance of the traditional criteria was sensitivity: 19.0%, specificity: 72.9%, positive predictive value (PPV): 1.6%, and missing rate: 81.0%. The optimal cut-off for MPC was 40.7%. Based on this cut-off value, the performance was sensitivity: 54.8%, specificity: 81.0%, PPV: 6.1%, and missing rate: 45.2%. Moreover, hemoglobin A1c, insulin treatment, and family history of diabetes have poor discrimination between MODY and young-onset type 2 diabetes. The MPC is better than traditional criteria in terms of both sensitivity and PPV. To ensure more MODY patients benefit from optimal treatment, we therefore suggest that routine genetic testing be performed on all type 2 diabetes patients who are between the ages of 15 and35 years and have MPC probability value over 40.7%.

Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus.

Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. The presence of clinical features of MODY and negative results for three autoantibody markers of T1DM in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). A 12 variants were classified as P/LP while 12 were interpreted as variant of unknown significance (VUS). Nine of the pathogenic or likely pathogenic variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All of the variants, except one, showed heterozygotic inheritance. This study screened mutations in the 14 MODY-related genes and the regulatory factor X6 (RFX6) gene in Turkish children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes.

FRI637 Missed MODY With Complex Mutation

Abstract Disclosure: S. Bulchandani: None. S. Majety: None. P. Kundra: None. Introduction: The prevalence range of Maturity-Onset Diabetes of the Young (MODY) is 1-5% among all patients diagnosed with diabetes. Strong family history of diabetes is suggestive of autosomal dominant inheritance. The symptoms of MODY range from mild asymptomatic hyperglycemia to overt insulinopenia requiring insulin therapy. Clinical Case: 33-year-old male presented to the endocrinology clinic for evaluation. He was diagnosed with type 2 diabetes mellitus at the age of 13 years and was initially treated with insulin which was subsequently transitioned to repaglinide and metformin. Reported history of hypoglycemia at birth in self and recently born daughter. Family History was significant for diabetes mellitus diagnosed in biological father at the age of 16 years. Genetic testing for monogenic diabetes revealed pathogenic variant in hepatocyte nuclear factor 4 alpha (HNF4a) and variant of unknown significance in Paired Box Gene 4 (PAX4). Therapy was switched to glipizide 2.5 mg orally which resulted in adequate glycemic control. Genetic testing was recommended for his daughter. Conclusion: MODY is a rare condition and because of its wide clinical presentation, it is common for it to be missed. There are about 14 subtypes of MODY with different genetic mutations, each affecting the beta cell function in a different way. Our case is unique given that our patient had two genetic mutations. Amongst all forms of MODY, HNF4a with a prevalence of 5% to 10% is the third most common mutation of MODY. PAX4 is a transcription factor that is critical for the formation of beta cells, and is important as a regulator in commitment of progenitor cells to mature islet cells. Mutations in PAX gene associated with monogenic diabetes were first identified in two patients of Thai origin, who did not present with mutations in the other known MODY genes. There should be high vigilance and low threshold for genetic testing for MODY in patients who have high likelihood of possessing a form of MODY, particularly as the treatment can be tailored to the clinical presentation of the patient.

SAT081 Maturity Onset Diabetes Of The Young (MODY) Due To A New BLK Gene Mutation

Abstract Disclosure: D. Taha: None. R. Thirunagari: None. A. Adhikari: None. Background: The BLK gene is a tyrosine protein kinase involved in cell proliferation and differentiation. It has been identified as a modulator of beta cell function and plays a role in the regulation of insulin synthesis and secretion. We describe the case of a patient presenting with prediabetes associated with a heterozygous c.1366 C>T of the BLK gene. Case Report: We report a 10 year old Asian female who presented with a hemoglobin A1c (HbA1c) level of 6.1% (4.0-5.7), within prediabetes range. Her weight was 44 kg (Z score 1.34), height 148.2 cm (Z score 1.52) and BMI was 20 kg/m2 (85th percentile; Z score 1.06). She had no acanthosis nigricans by exam and she was at early Tanner stage 2 of puberty. Initial evaluation revealed normal C-Peptide level of 2.1 ng/mL (0.9-6.9), normal insulin level of 21.1 mcUnits/mL (3 - 25). She had normal complete blood count and comprehensive metabolic profile, and normal thyroid function tests. Glutamic acid decarboxylase (GAD65) antibodies and islet cell antibodies were negative. She had an oral glucose tolerance test which revealed a fasting glucose level of 101 mg/dL and a 2-hour glucose level of 158 mg/dL. Lipid profile was normal. She was advised regarding healthy lifestyle changes and her HbA1c level was stable. She was lost to follow-up until 16 years of age when she presented with irregular menstrual cycles and was diagnosed with polycystic ovary syndrome. Her HbA1c was elevated at 6.3% with a normal insulin level. Cortisol and thyroid function tests were normal. Pancreatic antibodies including GAD65, IA-2, insulin antibodies, islet cell antibodies, and zinc transporter 8 antibodies, were negative. C-peptide level was normal at 4.3 ng/mL (1.1-4.4). Family history was significant for patient’s father and paternal grandmother having diabetes and taking Metformin. Patient’s father was diagnosed with diabetes at 13 years of age. Maturity onset diabetes of the young (MODY) panel/ sequencing and deletion/duplication analysis was performed at GeneDx and revealed that she is heterozygous for a c.1366 C>T; p.Arg456Cys (R456C) variant in exon 13 of the BLK gene. This variant has not been previously published as a pathogenic or benign variant to our knowledge. No additional variants were identified in any of the MODY genes on this panel (ABCC 8, APPL1, CEL, GCK, GLUD1, HADH, HNF1A, HNF 1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1). Conclusion: Variants of the BLK gene have been reported in association with autosomal dominant MODY, type 11. We report a pediatric patient presenting with MODY prediabetes associated with a heterozygous c.1366 C>T; p.R456C variant in the BLK gene. To our knowledge, this variant has not been previously reported in MODY patients. We propose that this is a pathogenic variant and review this rare MODY form. Presentation: Saturday, June 17, 2023

Prevalence of maturity-onset diabetes of the young in phenotypic type 2 diabetes in young adults: a nationwide, multi-center, cross-sectional survey in China.

Maturity-onset diabetes of the young (MODY) is the most common monogenic diabetes. The aim of this study was to assess the prevalence of MODY in phenotypic type 2 diabetes (T2DM) among Chinese young adults. From April 2015 to October 2017, this cross-sectional study involved 2429 consecutive patients from 46 hospitals in China, newly diagnosed between 15 years and 45 years, with T2DM phenotype and negative for standardized glutamic acid decarboxylase antibody at the core laboratory. Sequencing using a custom monogenic diabetes gene panel was performed, and variants of 14 MODY genes were interpreted as per current guidelines. The survey determined 18 patients having genetic variants causing MODY (6 HNF1A , 5 GCK , 3 HNF4A , 2 INS , 1 PDX1 , and 1 PAX4 ). The prevalence of MODY was 0.74% (95% confidence interval [CI]: 0.40-1.08%). The clinical characteristics of MODY patients were not specific, 72.2% (13/18) of them were diagnosed after 35 years, 47.1% (8/17) had metabolic syndrome, and only 38.9% (7/18) had a family history of diabetes. No significant difference in manifestations except for hemoglobin A1c levels was found between MODY and non-MODY patients. The prevalence of MODY in young adults with phenotypic T2DM was 0.74%, among which HNF1A -, GCK -, and HNF4A -MODY were the most common subtypes. Clinical features played a limited role in the recognition of MODY.

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland.

The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. Thevariant caused lower 30-min insulin (β=-232pmol/L, βSD=-0.695, P=4.43×10-4) and higher 30-min glucose (β=1.20mmol/L, βSD=0.441, P=0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P=7.24×10-6) and HbA1c (β=0.113 HbA1c%, βSD=0.205, P=7.84×10-3). The variant explained 2.5% of diabetes variance in Greenland. The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations. Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation.

Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort.

Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established. Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population. Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics. Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.

Maturity-onset diabetes of the young in a large Portuguese cohort.

Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.

Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history in China

PurposeEarly-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort.MethodsOf 6470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case–control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 early-onset T2D patients without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP, and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families.ResultsCompared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m2, P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes (KLF11, GCK, ABCC8, PAX4, BLK and HNF1A) of MODY.ConclusionseDia3 patients had unique clinical features. Known MODY genes were not common causes in these patients.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

How do I diagnose Maturity Onset Diabetes of the Young in my patients?

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria‐based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.

Precision Diagnosis of Maturity-Onset Diabetes of the Young with Next-Generation Sequencing: Findings from the MODY-IST Study in Adult Patients.

Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.

Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population.

BACKGROUNDMonogenic forms of diabetes (MFD) are single gene disorders. Their diagnosis is challenging, and symptoms overlap with type 1 and type 2 diabetes.AIMTo identify the genetic variants responsible for MFD in the Pakistani population and their frequencies.METHODSA total of 184 patients suspected of having MFD were enrolled. The inclusion criterion was diabetes with onset below 25 years of age. Brief demographic and clinical information were taken from the participants. The maturity-onset diabetes of the young (MODY) probability score was calculated, and glutamate decarboxylase ELISA was performed. Antibody negative patients and features resembling MODY were selected (n = 28) for exome sequencing to identify the pathogenic variants. RESULTSA total of eight missense novel or very low-frequency variants were identified in 7 patients. Three variants were found in genes for MODY, i.e. HNF1A (c.169C>A, p.Leu57Met), KLF11 (c.401G>C, p.Gly134Ala), and HNF1B (c.1058C>T, p.Ser353Leu). Five variants were found in genes other than the 14 known MODY genes, i.e. RFX6 (c.919G>A, p.Glu307Lys), WFS1 (c.478G>A, p.Glu160Lys) and WFS1 (c.517G>A, p.Glu173Lys), RFX6 (c.1212T>A, p.His404Gln) and ZBTB20 (c.1049G>A, p.Arg350His).CONCLUSIONThe study showed wide spectrum of genetic variants potentially causing MFD in the Pakistani population. The MODY genes prevalent in European population (GCK, HNF1A, and HNF4a) were not found to be common in our population. Identification of novel variants will further help to understand the role of different genes causing the pathogenicity in MODY patient and their proper management and diagnosis.

Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age.

Background Maturity-onset diabetes of the young (MODY) is commonly misdiagnosed as type 1 or type 2 diabetes. Common reasons for misdiagnosis are related to limitations in genetic testing. A precise molecular diagnosis is essential for the optimal treatment of patients and allows for early diagnosis of their asymptomatic family members. Objective The aim of this study was to identify rare monogenic variants of common MODY genes in Japanese pediatric patients. Methods We investigated 45 Japanese pediatric patients based on the following clinical criteria: development of diabetes before 17 years of age, a family history of diabetes, testing negative for glutamate decarboxylase-65 (GAD 65) antibodies and insulinoma-2-associated autoantibodies (IA-2A), no significant obesity, and evidence of endogenous insulin production. Genetic screening for MODY1 (HNF4α), MODY2 (GCK), MODY3 (HNF1α), and MODY5 (HNF1β) was performed by direct sequencing followed by multiplex ligation amplification assays. Results We identified 22 missense variants (3 novel variants) in 27 patients (60.0%) in the GCK, HNF4α, and HNF1α genes. We also detected a whole exon deletion in the HNF1β gene and an exon 5–6 aberration in the GCK gene, each in one proband (4.4%). There were a total of 29 variations (64.4%), giving a relative frequency of 53.3% (24/45) for GCK, 2.2% (1/45) for HNF4α, 6.7% (3/45) for HNF1α, and 2.2% (1/45) for HNF1β genes. Conclusions Clinicians should consider collecting and assessing detailed clinical information, especially regarding GCK gene variants, in young antibody-negative patients with diabetes. Correct molecular diagnosis of MODY better predicts the clinical course of diabetes and facilitates individualized management.

Identification of Maturity-Onset-Diabetes of the Young (MODY) mutations in a country where diabetes is endemic

Genetic variants responsible for Maturity-Onset-Diabetes of the Young (MODY) in Kuwait were investigated. A newly established a National Referral Clinic, the Dasman Diabetes Institute (DDI-NRC), assessed forty-five members from 31 suspected MODY families by whole exome sequencing. Thirty-three of the 45 samples were independently sequenced at the DDI-NRI, Exeter University, UK (https://www.diabetesgenes.org/) using targeted 21-gene panel approach. Pathogenic mutations in GCK, HNF1A, HNF1B, HNF4A, and PDX1 confirmed MODY in 7 families, giving an overall positivity rate of 22.6% in this cohort. Novel variants were identified in three families in PDX1, HNF1B, and HNF1B. In this cohort, Multiplex Ligation-dependent Probe Amplification assay did not add any value to MODY variant detection rate in sequencing negative cases. In highly selected familial autoantibody negative diabetes, known MODY genes represent a minority and 77.3% of the familial cases have yet to have a causal variant described.

The Epidemiology and Genetic Analysis of Children With Idiopathic Type 1 Diabetes in the State of Qatar.

ContextIdiopathic type 1 diabetes is characterized by the absence of autoantibodies and the underlying mechanisms are not clear.ObjectiveWe aimed to study the epidemiology, describe the clinical characteristics, and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes.MethodsThis was a prospective study of type 1 diabetes patients attending Sidra Medicine from 2018 to 2020. Autoantibodies (GAD65, IAA, IA-2A, and ZnT8) were measured and genetic testing was undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes were compared with patients with autoimmune type 1 diabetes.ResultsOf 1157 patients with type 1 diabetes, 63 were antibody-negative. Upon genome sequencing, 4 had maturity onset diabetes of the young (MODY), 2 had Wolfram syndrome, 1 had H syndrome, and 3 had variants of uncertain significance in MODY genes; 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10 to 14 years. C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average body mass index was in the normal range and 33% of the patients had a history of diabetic ketoacidosis (DKA).ConclusionFour percent of the children had idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the 2 groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is unknown but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

Identification of candidate gene variants of monogenic diabetes using targeted panel sequencing in early onset diabetes patients

IntroductionMonogenic diabetes is attributed to genetic variations in a single gene. Maturity-onset diabetes of the young (MODY) is the most common phenotype associated with monogenic diabetes, but is frequently misdiagnosed...

Case Report and Literature Review: Homozygous DNAJC3 Mutation in a Saudi Family Causing Maturity Onset Diabetes of the Young (MODY), Hypothyroidism, Short Stature, Neurodegeneration, and Hearing Loss

Introduction: Monogenic diabetes results from a mutation in single gene, predominantly inherited and typically affects the young. DNAJC3 acts in attenuating endoplasmic reticulum stress and is found in abundance in pancreatic tissue. Clinical Case: We report a homozygous DNAJC3 mutation in two siblings of a consanguineous Saudi family. A 3-year boy presented with short stature and thyroid nodule; lab findings confirmed hypothyroidism, with TSH 27.8 and FT4 6.7 (n: TSH:0.35-4.94 mIU/L, FT4:9.0-19 pmol/L). Subsequently, L-thyroxine was started. GH stimulation test was normal. He was severely short; 80.5 cm (< 1 percentile, -3.79 SD). The patient developed sensorineural hearing loss (SNHL) at 6 years. He had low intellectual function and weak school performance. GH treatment was postponed to age 9 due to strong family history of DM. At that point, the patient developed progressive ataxic gait, for which he had muscle biopsy that excluded mitochondrial disease and workup for multiple sclerosis, which was excluded. Brain and spine MRI showed prominent neurodegeneration in subcortical white matter. At age 11, the patient developed DM, 4 years after GH treatment initiation. DM autoimmune markers were negative on multiple occasions. Lifestyle modification was initiated but soon required basal and bolus insulin therapy. Whole exome sequencing revealed homozygous DNAJC3 mutation, which explained his clinical presentation. At age of 17, adult height was 141 cm (Z-score: -5.87). His older brother had similar history discovered retrospectively but did not develop neurodegeneration or ataxia from the same DNAJC3 mutation. Literature Review: Literature review revealed six individuals with homozygous DNAJC3 mutation. All patients developed DM, with onset ranging from 11 to 19 years, highly suggestive of MODY. Other endocrine manifestations included short stature, and hypothyroidism due to primary etiology; in view of elevated TSH levels, vs. being secondary, as suggested by the authors. All patients had mitochondrial disease workups and was excluded. Variable neurodegeneration degrees are described; SNHL, progressive ataxia, sensorimotor neuropathy, and cognitive deficits. MRI findings showed atrophy of cerebellum, brainstem, cervical spinal cord, and hyperintense T2 lesions typical of neurodegeneration. Conclusion: Homozygous DNAJC3 gene mutation fits MODY criteria, we propose recognizing it as one of the known MODY gene mutations. Hypothyroidism is due to primary etiology, evident by TSH spikes. Physicians evaluating mitochondrial disease in patients with a constellation of SNHL, DM, hypothyroidism, neurodegeneration, and short stature should suspect DNAJC3 as one differential diagnosis. GH treatment must be initiated cautiously, with close monitoring due to its known diabetogenic effect, especially in DNAJC3 mutations, defective endoplasmic stress attenuation mechanism.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Genetic characterization of suspected MODY patients in Pakistan by next generation sequencing—a pilot study

Maturity onset diabetes of the young (MODY) is the genetic form of diabetes inherited in autosomal dominant pattern. The diagnosis of MODY is challenging and confirmed by genetic testing. The objective of this study was to investigate MODY in Pakistani patients using next-generation sequencing. The next-generation sequencing was performed to know the cause of disease in 07 patients phenotypically suspected for MODY from Pakistan. These patients were selected based on the high probability score through MODY probability calculator. Only those genetic variants were retained which were having low frequency as per available data bases and their potential effects on protein as assessed by bioinformatics prediction tools. Four heterozygous variants were found among patients. This includes mutation in HNF1a gene (c.526+1G>A) that is already reported for causative for MODY type 3 which is most prevalent among all MODY sub-types. Other variants were identified in GCK (c.-45G>A), KLF11 (c.*96dupA), and CEL (c.1235C>T). This study was the first in Pakistan to investigate the MODY using next-generation sequencing for clinical applications. There is huge public health burden of diabetes in the country. The study identified mutation in one known MODY gene. More extensive studies involving large sample size are required in future.