Maturity onset diabetes of the young in India – a distinctive mutation pattern identified through targeted next‐generation sequencing. (7th August 2014)

• Record Type: Journal Article
• Authors: Chapla, Aaron; Mruthyunjaya, Mahesh Doddabelavangala; Asha, Hesarghatta Shyamasunder; Varghese, Denny; Varshney, Manika; Vasan, Senthil K.; Venkatesan, Padmanaban; Nair, Veena; Mathai, Sarah; Paul, Thomas Vizhalil; Thomas, Nihal
• Is Part Of: Clinical endocrinology. Volume 82:Number 4(2015:Apr.)
• Page Start: 533
• Page End: 542
• Publication Date: 2014-08-07
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1111/cen.12541
• Languages: English
• ISSNs: 0300-0664

Abstract

<abstract abstract-type="main" id="cen12541-abs-0001"> <title>Summary</title> <sec id="cen12541-sec-0001" sec-type="section"> <title>Objective</title> <p>To establish and utilize a Next‐Generation Sequencing (NGS)‐based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early‐onset diabetes.</p> </sec> <sec id="cen12541-sec-0002" sec-type="section"> <title>Patients and Methods</title> <p>Maturity onset diabetes of the young (MODY) genetic testing was carried out in 80 subjects of Asian Indian origin with young onset diabetes to identify mutations in a comprehensive panel of ten MODY genes. A novel multiplex polymerase chain reaction (PCR)‐based target enrichment was established, followed by NGS on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing.</p> </sec> <sec id="cen12541-sec-0003" sec-type="section"> <title>Results</title> <p>We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel. The identified mutations include p.H241Q, p.E59Q, c.‐162G>A 5′ UTR in <italic>NEUROD1</italic>, p.V169I cosegregating with c.493‐4G>A and c.493‐20C>T, p.E271K in <italic>HNF4A</italic>, p.A501S in <italic>HNF1A</italic>, p.E440X in <italic>GCK</italic>, p.V177M in <italic>PDX1</italic>, p.L92F in <italic>HNF1B</italic> and p.R31L in <italic>PAX4</italic> genes. Interestingly, two patients with <italic>NEUROD1</italic> mutation were also positive for the p.E224K mutation in <italic>PDX1</italic> gene. These patients with coexisting <italic>NEUROD1–PDX1</italic> mutations showed a marked reduction in glucose‐induced insulin secretion. All 24 subjects who had not met the clinical criteria of MODY were negative for the mutations. To the best of our knowledge, this is the first report of <italic>PDX1</italic>, <italic> HNF1B, NEUROD1</italic> and <italic>PAX4</italic> mutations from India.</p> </sec> <sec id="cen12541-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Multiplex PCR coupled with NGS provides a rapid, cost‐effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving <italic>NEUROD1</italic> and <italic>PDX1</italic> genes.</p> </sec> </abstract>