Genetic Characterization of MODY in Iranian Families Using Multigenerational-Based Whole-Exome Sequencing Approach

Maturity-onset diabetes of the young (MODY), a common type of monogenic diabetes caused by a pathogenic variant in a single gene, is characterized by starting at an early age, autosomal dominant inheritance, and decreased secretion of insulin. Despite its clinical importance, its accurate diagnosis is challenging, and it is often misdiagnosed as other types of diabetes. Therefore, understanding the genetic basis of MODY can improve diagnostic accuracy.

We initially performed genetic counseling for 2964 probands who visited the Yazd Diabetes Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran, between 2018 and 2022. Clinical assessments and pedigree analyses were conducted for the accurate clinical diagnosis and management of diabetes. Among these, 11 probands with unknown types of diabetes who met specific criteria, including an inheritance pattern across at least three generations, at least seven affected individuals, and probands being under age 55, were selected for whole-exome sequencing (WES). Finally, variants were verified by Sanger sequencing, pedigree analysis, and segregation analysis.

WES analysis detected pathogenic variants in two families, which confirmed MODY. Family 202 had a novel missense variant (GCK: c.484G > C; p.Gly162Arg; NM_000162.5). In Family 105, an extremely rare pathogenic frameshift variant (HNF1A: c.1136_1137del; p.Pro379ArgfsTer39; NM_000545.8) was identified. The segregation analyses of these variants also revealed that the variants largely co-segregated with the diabetes phenotype in their respective families.

This study clearly demonstrates the effectiveness of WES for the accurate identification of MODY subtypes in Iranian families. Moreover, these findings emphasize the need for further genetic screening programs in Iran to enhance MODY diagnosis, personalized treatment, and family genetic counseling.