Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India

Abstract Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

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Study of Thirteen Causal Genes in Turkish Patients with Clinically Suspected Maturity-Onset Diabetes of the Young (MODY) using a Targeted Next-Generation Sequencing Panel

10.21203/rs.3.rs-771448/v1 ◽

2021 ◽

Author(s):

Mustafa Dogan ◽

Recep Eroz ◽

Semih Bolu ◽

Hüseyin Yüce ◽

Alper Gezdirici ◽

...

Keyword(s):

Next Generation Sequencing ◽

Molecular Genetic ◽

Maturity Onset Diabetes ◽

Next Generation ◽

Molecular Defects ◽

Pathogenic Variants ◽

Onset Diabetes ◽

Effective Manner ◽

Long Term Treatment ◽

Generation Sequencing

Abstract Background: Maturity-onset diabetes of the young (MODY), which is the most common cause of monogenic diabetes, has an autosomal dominant pattern of inheritance and exhibits marked clinical and genetic heterogeneity. The aim of the current study was to investigate molecular defects in patients with clinically suspected MODY using a next-generation sequencing (NGS)-based targeted gene panel. Candidate patients with clinical suspicion of MODY and their parents were included in the study. Molecular genetic analyses were performed on genomic DNA by using NGS. A panel of thirteen MODY-related genes involving ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1 was designed and subsequently implemented to screen 44 patients for genetic variants. Ten different pathogenic or likely pathogenic variants were identified in MODY-suspected patients, with a diagnostic rate of 22.7%. Eight variants of uncertain significance were also detected. Four novel pathogenic or likely pathogenic variants were detected in the genes GCK (c.1301G>T [p.Cys434Phe]), HNF1A (c.505_506delAA [p.Lys169AlafsTer18]), ABCC8 (c.3584C>T [p.Thr1195Ile]), and CEL (c.679-1G>A). Intriguingly, we were able to detect variants associated with rare forms of MODY in our study population. Our results suggest that in heterogenous diseases such as MODY, NGS analysis enables accurate identification of underlying molecular defects in a timely and cost-effective manner. Although MODY accounts for 1–2% of all diabetic cases, molecular genetic diagnosis of MODY is necessary for optimal long-term treatment and prognosis as well as for effective genetic counseling.

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Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

Frontiers in Endocrinology ◽

10.3389/fendo.2021.684018 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mariam Moalla ◽

Wajdi Safi ◽

Maab Babiker Mansour ◽

Mohamed Hadj Kacem ◽

Mona Mahfood ◽

...

Keyword(s):

Autoimmune Diabetes ◽

Clinical Investigation ◽

Direct Sequencing ◽

Short Review ◽

Tunisian Population ◽

Maturity Onset Diabetes ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Onset Diabetes ◽

And Function

Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

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Causal variants in Maturity Onset Diabetes of the Young (MODY) – A systematic review

BMC Endocrine Disorders ◽

10.1186/s12902-021-00891-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ibrar Rafique ◽

Asif Mir ◽

Muhammad Arif Nadeem Saqib ◽

Muhammad Naeem ◽

Luc Marchand ◽

...

Keyword(s):

Middle Eastern ◽

Maturity Onset Diabetes ◽

Dominant Type ◽

Pathogenic Variants ◽

Search Terms ◽

Onset Diabetes ◽

Causal Variants ◽

Autosomal Dominant Type

Abstract Background Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date. Methods We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes. Results The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries. Conclusions We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.

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Abstract #314: Maturity Onset Diabetes of the Young: A Case Report

Endocrine Practice ◽

10.1016/s1530-891x(20)45022-0 ◽

2016 ◽

Vol 22 ◽

pp. 94

Author(s):

Deepa Philip ◽

Laura Chalmers

Keyword(s):

Case Report ◽

Maturity Onset Diabetes ◽

Onset Diabetes

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Maturity-onset Diabetes of the Young (MODY): molekulargenetische und klinische Klassifizierung von 156 Patienten mit Diabetes mellitus zur verbesserten therapeutischen Entscheidungsfindung

Diabetologie und Stoffwechsel ◽

10.1055/s-0031-1277398 ◽

2011 ◽

Vol 6 (S 01) ◽

Author(s):

S Fees ◽

G Wildhardt ◽

AJ Driesel ◽

D Steinberger

Keyword(s):

Diabetes Mellitus ◽

Maturity Onset Diabetes ◽

Onset Diabetes

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Diagnostik auf Maturity-onset Diabetes of the Young (MODY) mit next generation sequencing: Opportunitäten für eine rationale und verbesserte Versorgung Betroffener

Diabetologie und Stoffwechsel ◽

10.1055/s-0033-1341859 ◽

2013 ◽

Vol 8 (S 01) ◽

Author(s):

MK Balogh ◽

G Wildhardt ◽

AJ Driesel ◽

D Steinberger

Keyword(s):

Next Generation Sequencing ◽

Maturity Onset Diabetes ◽

Next Generation ◽

Onset Diabetes ◽

Generation Sequencing

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Diabetes mellitus bei Kindern und Jugendlichen

Kinder- und Jugendmedizin ◽

10.1055/s-0038-1625649 ◽

2007 ◽

Vol 7 (04) ◽

pp. 203-208

Author(s):

Wieland Kiess ◽

Thomas Kapellen ◽

Angela Galler

Keyword(s):

Diabetes Mellitus ◽

Diabetes Mellitus Typ 2 ◽

Maturity Onset Diabetes ◽

Genetische Diagnostik ◽

Diabetes Mellitus Typ 1 ◽

Genetische Faktoren ◽

Onset Diabetes ◽

Inherited Diabetes

ZusammenfassungGene spielen bei der Pathogenese des Diabetes mellitus eine wichtige Rolle. Die häufigste Form bei Kindern und Jugendlichen ist der Diabetes mellitus Typ 1. Bei vorhandener genetischer Prädisposition kann durch verschiedene Umweltfaktoren eine Autoimmunreaktion ausgelöst werden, welche durch Zerstörung der Betazellen zum Insulinmangel und somit zum Diabetes mellitus Typ 1 führt. Beim Diabetes mellitus Typ 2, welcher bei der zunehmenden Adipositas im Kindes- und Jugendalter in den letzten Jahren in Deutschland häufiger zu beobachten ist, spielen genetische Faktoren eine entscheidende Rolle. Der Diabetes mellitus Typ 2 wird polygen vererbt. Bisher liegen jedoch nur unzureichende Daten vor, um eine genetische Diagnostik in der Praxis sinnvoll erscheinen zu lassen. Bei einer Reihe von weiteren Diabetestypen ist deren genetische Ursache in den letzten Jahrzehnten geklärt worden. Eine genetische Diagnostik ist in diesen Fällen notwendig und sinnvoll. Der Maturity Onset Diabetes of the Young (MODY) fällt meist durch seine im Vergleich zum Diabetes mellitus Typ 1 mildere Verlaufsform auf und wird mit einer Häufigkeit von 5–10% aller Diabetesformen beziffert. Der MODY Typ 2 wird durch eine Mutation im Glukokinase-Gen hervorgerufen, der MODY Typ 3 durch eine Mutation im HNF-1α-Gen. Der mitochondriale Diabetes mellitus wird aufgrund der häufig auftretenden Schwerhörigkeit auch als MIDD (Maternally Inherited Diabetes and Deafness) bezeichnet und durch Mutationen im mitochondrialen Genom hervorgerufen. Weiterhin wurden in den letzten Jahren verschiedene Genmutationen beim sehr seltenen neonatalen Diabetes mellitus (transienter und permanenter neonataler Diabetes mellitus) aufgeklärt.

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