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

Abstract

BackgroundMaturity-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.MethodsIn 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0528-6) contains supplementary material, which is available to authorized users.

Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: Dominance of maternal inheritance

“…The first two groups of etiologies can be addressed by employing targeted massive parallel sequencing of known MODY genes as a screening tool, and by performing the whole‐exome/‐genome sequencing studies on the remaining patients. In fact, recent studies utilizing the targeted high‐throughput sequencing have shown that, in patients with MODY or with type 2 diabetes, mutations in ABCC8 could be more frequent than those in HNA4A , HNF1B , or INS making this gene as one of the candidates of major MODY genes.…”

“…2018) for MODY. Of these, the common four genes, HNF1A , HNF4A , GCK , and HNF1B have accounted for the majority of identified MODY mutations, although, recently, ABCC8 has emerged as a relatively common causative gene in certain populations . Reported breakdowns of mutations vary widely depending on the ethnicity and the route of ascertainment .…”

“…Of these, the common four genes, HNF1A, HNF4A, GCK, and HNF1B have accounted for the majority of identified MODY mutations, 1 although, recently, ABCC8 has emerged as a relatively common causative gene in certain populations. 2 Reported breakdowns of mutations vary widely depending on the ethnicity and the route of ascertainment. 3 Generally, higher detection rates have been reported from European countries; 66%-97% in the United Kingdom, Germany, Italy, Spain, or Greece, and somewhat lower (38%-49%) in the Netherlands, Czech Republic, or Denmark.…”

Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation

“…More recently, because targeted next‐generation sequencing has become widely available and more comprehensive genetic studies have been performed in patients assumed to have type 1 diabetes, mutations in the ABCC8 have been found to be the causative factor in a significant percentage of patients with MODY. Interestingly, a comprehensive genomic analysis of 152 individuals with clinically diagnosed MODY in South India showed that mutations in the ABCC8 gene were the second most common cause in this population …”

Precision Diabetes Is Slowly Becoming a Reality

“…We also identified MODY 5 in some of our patients [76]. We have recently reported on a comprehensive analysis of all 14 MODY genes and have also reported on what is likely to be a new MODY gene, with a mutation in the NKX6-1 gene, located on chromosome 7 [77]. …”