Comprehensive Maturity Onset Diabetes of the Young (MODY) Gene Screening in Pregnant Women with Diabetes in India.

Pregnant women with diabetes may have underlying beta cell dysfunction due to mutations/rare variants in genes associated with Maturity Onset Diabetes of the Young (MODY). MODY gene screening would reveal those women genetically predisposed and previously unrecognized with a monogenic form of diabetes for further clinical management, family screening and genetic counselling. However, there are minimal data available on MODY gene variants in pregnant women with diabetes from India. In this study, utilizing the Next generation sequencing (NGS) based protocol fifty subjects were screened for variants in a panel of thirteen MODY genes. Of these subjects 18% (9/50) were positive for definite or likely pathogenic or uncertain MODY variants. The majority of these variants was identified in subjects with autosomal dominant family history, of whom five were in women with pre-GDM and four with overt-GDM. The identified variants included one patient with HNF1A Ser3Cys, two PDX1 Glu224Lys, His94Gln, two NEUROD1 Glu59Gln, Phe318Ser, one INS Gly44Arg, one GCK, one ABCC8 Arg620Cys and one BLK Val418Met variants. In addition, three of the seven offspring screened were positive for the identified variant. These identified variants were further confirmed by Sanger sequencing. In conclusion, these findings in pregnant women with diabetes, imply that a proportion of GDM patients with autosomal dominant family history may have MODY. Further NGS based comprehensive studies with larger samples are required to confirm these finding.

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

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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 NEUROD1, p.V169I cosegregating with c.493-4G>A and c.493-20C>T, p.E271K in HNF4A, p.A501S in HNF1A, p.E440X in GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes. Interestingly, two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with coexisting NEUROD1-PDX1 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 PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. CONCLUSIONS: 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 NEUROD1 and PDX1 genes.