Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, No. 4, Conran Smith Road, Gopalapuram, Chennai, Tamil Nadu, 600 086, India.
Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
BMC Med Genet. 2018 Feb 13;19(1):22. doi: 10.1186/s12881-018-0528-6.
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.
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.
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.
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.
青年发病型糖尿病（MODY）是一种早发的、常染色体显性的非胰岛素依赖型糖尿病。MODY 的基因诊断可以改变患者的管理方式。先前关于 MODY 遗传易感性的数据主要来自欧洲人群的家族研究。
在这项研究中，我们对来自印度的 289 个人进行了全面的基因组分析，其中包括 152 例临床诊断为 MODY 的病例，以鉴定已知 MODY 基因中的变异。此外，我们还分析了外显子组数据，以鉴定先前未涉及 MODY 的基因中可能与 MODY 相关的变异。还对 MODY 相关变异进行了功能验证。
我们发现 MODY3（HNF1A；7.2%）是最常突变的，其次是 MODY12（ABCC8；3.3%）。它们共占约 11%的病例。除了已知的 MODY 基因外，我们还报告了 RFX6、WFS1、AKT2、NKX6-1 中可能导致 MODY 发生的变异。对 NKX6-1 变异的功能评估表明，它们的功能受到了损害。
我们的研究结果表明，HNF1A 和 ABCC8 是印度南部最常突变的 MODY 基因。此外，我们还提供了其他与 MODY 相关的基因的证据，如 NKX6-1，这些证据需要进一步验证。
