identification of pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India

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

• Viswanathan Mohan†Email author,
• Venkatesan Radha†,
• Thong T. Nguyen†,
• Eric W. Stawiski†,
• Kanika Bajaj Pahuja,
• Leonard D. Goldstein,
• Jennifer Tom,
• Ranjit Mohan Anjana,
• Monica Kong-Beltran,
• Tushar Bhangale,
• Suresh Jahnavi,
• Radhakrishnan Chandni,
• Vijay Gayathri,
• Paul George,
• Na Zhang,
• Sakthivel Murugan,
• Sameer Phalke,
• Subhra Chaudhuri,
• Ravi Gupta,
• Jingli Zhang,
• Sam Santhosh,
• Jeremy Stinson,
• Zora Modrusan,
• V. L. Ramprasad,
• Somasekar SeshagiriEmail authorView ORCID ID profile and
• Andrew S. PetersonEmail author

†Contributed equally

BMC Medical GeneticsBMC series – open, inclusive and trusted201819:22

https://doi.org/10.1186/s12881-018-0528-6

©  The Author(s). 2018

Received: 25 August 2017

Accepted: 19 January 2018

Published: 13 February 2018

Open Peer Review reports

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

MODYDiabetesExomeGenomics analysisNKX6–1