Maturity onset diabetes of the young in India – a distinctive mutation pattern identified through targeted next‐generation sequencing

Chapla, Aaron; Mruthyunjaya, Mahesh Doddabelavangala; Asha, Hesarghatta Shyamasunder; Varghese, Denny; Varshney, Manika; Vasan, Senthil K.; Venkatesan, Padmanaban; Nair, Veena; Mathai, Sarah; Paul, Thomas; Nicolaï, Thomas

doi:10.1111/cen.12541

Cited by 110 publications

(91 citation statements)

References 35 publications

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“…we have identified six (12%) different HNF1B gene mutations and whole-gene deletion 82 . Recently, Chapla et al 83 carried out MODY genetic testing among young onset diabetic patients of AsianIndian origin, using Ion Torrent next-generation sequencing (NGS) technology. About 19% of the 56 clinically dignosed MODY subjects carried MODY mutations in one of the MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1 and PAX4).…”

Section: Studies On Mody In Indiamentioning

confidence: 99%

Genetic Basis of Monogenic Diabetes

Radha¹,

Mohan²

2017

Current Science

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Advances in the understanding of monogenic causes of diabetes and the discovery of single-gene mutations responsible for different phenotypes have greatly increased our knowledge of -cell physiology. Such advances have had implications for the individual patient diagnosed with the specific monogenic cause of diabetes, especially in maturity onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). Genetic diagnosis of MODY is also likely to have important prognostic and therapeutic implications in majority of the patients with confirmed HNF1A and HNF4A mutations. Genetic screening and analyses have helped several neonatal infants carrying mutations in the KCNJ11 and ABCC8 genes to shift from insulin treatment to oral sulphonylurea drugs. The progress in genomics of monogenic diabetic forms has helped in translating the discoveries from bench to bedside in clinical care. Therefore, there is an urgent need to incorporate genetic testing for the genes implicated in monogenic diabetes like MODY and NDM in the diabetes clinics. Discoveries in genetic research methodology and understanding of genetic etiology will have great translational implications for disease treatment and follow-up.

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Section: Studies On Mody In Indiamentioning

confidence: 99%

Genetic Basis of Monogenic Diabetes

Radha¹,

Mohan²

2017

Current Science

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“…В последние годы для установления генетической природы моноген-ных заболеваний активно применяется технология секвенирования нового поколения, которая позво-ляет проводить одновременный анализ нескольких генов-кандидатов моногенных заболеваний. К на-стоящему времени в мире проведено несколько ис-следований структуры MODY с использованием технологии секвенирования нового поколения [3][4][5][6][7]. Важным преимуществом данного метода перед методом прямого секвенирования является возмож-ность активного выявления случаев дигенного и олигогенного наследования.…”

Section: сведения об авторахunclassified

Clinical and molecular genetic characteristics of MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing

Гиоева¹,

Zubkova²,

Тихонович³

et al. 2017

Probl Endokrinol (Mosk)

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The diagnosis of MODY should be verified by molecular genetic analysis. Recently the introduction of next-generation sequencing, allowing simultaneous analysis of several candidate genes, greatly facilitates the diagnosis of monogenic diseases including MODY. In addition, the simultaneous analysis of several candidate genes allows to identify cases with digenic and oligogenic inheritance. In this work we present the first description of MODY cases with digenic and oligogenic inheritance in our country.Aim — to characterize MODY cases with digenic and oligogenic inheritance as defined by targeted next-generation sequencing.Material and methods. 256 subjects (age range, 0.3—25 yrs; males, n=149, females, n=107) were included in the study. The patients fulfilled the following MODY criteria: diabetes or intermediate hyperglycemia, absence of β-cell autoimmunity (ICA, GAD, IA2, IAA antibodies), preserved C-peptide secretion. Molecular genetic analysis was performed by next-generation sequencing using custom Ion Ampliseq gene panel and PGM semiconductor sequencer (Ion Torrent). All mutations were confirmed by Sanger sequencing.Results. 10 patients (8 probands, 1 sibling and 1 parent) showed digenic inheritance of MODY: 3 patients with combination of mutations in 2 candidate genes of MODY, 7 — in a candidate genes of MODY and another gene, associated with diabetes mellitus. In 1 case (sibling) showed oligogenic inheritance (mutations in GCK, HNF4A and INSR genes). Seven of the identified mutations were not previously described.Conclusion. Next-generation sequencing is useful in identifying of MODY cases with digenic and oligogenic inheritance, which is extremely important with potentially modifying effect on the phenotype.

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“…However, till recently, the molecular diagnosis of these monogenic disorders included sequential screening of only a few related genes based on the phenotype [4]. Moreover, due to the prohibitive cost and limitations associated with the scalability of Sanger sequencing, most diagnostic laboratories screen for hepatocyte nuclear factor 1alpha (HNF1A), glucokinase (GCK) and hepatocyte nuclear factor 4 alpha (HNF4A) mutations in MODY [5] or the ATPsensitive potassium channels, KCNJ11 and ABCC8, and the insulin gene (INS) mutations in neonatal diabetes [3]. Only a few of those patients who test negative for mutations in these genes are subjected to further genetic testing of the less common monogenic forms of diabetes [4].…”

Section: Maturity Onset Of Diabetes Of Youngmentioning

confidence: 99%

“…Recent studies utilizing next-generation sequencing (NGS)-based parallel multi-gene testing have shown promising results [3,5], and the testing has been proven to find the genetic cause even with limited phenotypic information and also in the absence of characteristic features in monogenic diabetes-related subtypes [12]. Further, with the identification of digenic mutations in MODY [5] and also often with overlapping clinical features [7], project the need for parallel multigene testing in monogenic diabetes which could provide a comprehensive genetic portrait.…”

Section: Neonatal Diabetes Mellitusmentioning

confidence: 99%