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

BMC Med Genet. 2018 Feb 13;19(1):22. doi: 10.1186/s12881-018-0528-6.

Abstract

Background: Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin.

Methods: In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed.

Results: We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6-1 that may contribute to development of MODY. Functional assessment of the NKX6-1 variants showed that they are functionally impaired.

Conclusions: Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6-1, and these require further validation.

Keywords: Diabetes; Exome; Genomics analysis; MODY; NKX6–1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / diagnosis*
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Exome
  • Female
  • Gene Library
  • Genetic Predisposition to Disease / epidemiology*
  • Genomics
  • Glycated Hemoglobin / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • India / epidemiology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Regulatory Factor X Transcription Factors / genetics
  • Regulatory Factor X Transcription Factors / metabolism
  • Sequence Analysis, DNA
  • Sulfonylurea Receptors / genetics
  • Sulfonylurea Receptors / metabolism
  • Young Adult

Substances

  • ABCC8 protein, human
  • Glycated Hemoglobin A
  • Hepatocyte Nuclear Factor 1-alpha
  • Homeodomain Proteins
  • Membrane Proteins
  • NKX6-1 protein, human
  • Regulatory Factor X Transcription Factors
  • Rfx6 protein, human
  • Sulfonylurea Receptors
  • wolframin protein
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt

Supplementary concepts

  • Mason-Type Diabetes