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

Area of Science:

• Medical Genetics
• Endocrinology
• Genomic Medicine

Background:

• Maturity-onset diabetes of the young (MODY) is a monogenic diabetes type often misdiagnosed.
• Accurate MODY diagnosis is crucial for effective management and genetic counseling.
• Genetic underpinnings of MODY are key to improving diagnostic accuracy.

Purpose of the Study:

• To investigate the genetic basis of MODY in Iranian families.
• To identify pathogenic variants causing MODY using whole-exome sequencing (WES).
• To enhance diagnostic accuracy and inform personalized treatment strategies for MODY.

Main Methods:

• Genetic counseling and clinical assessments for 2964 probands.
• Selection of 11 probands meeting specific MODY criteria for WES.
• Variant verification through Sanger sequencing, pedigree, and segregation analyses.

Main Results:

• Whole-exome sequencing identified pathogenic variants in two Iranian families, confirming MODY.
• A novel missense variant in GCK (c.484G>C; p.Gly162Arg) was found in Family 202.
• A rare frameshift variant in HNF1A (c.1136_1137del; p.Pro379ArgfsTer39) was identified in Family 105.
• Segregation analyses confirmed the co-segregation of variants with the diabetes phenotype.

Conclusions:

• Whole-exome sequencing is effective for identifying MODY subtypes in Iranian populations.
• Findings highlight the need for expanded genetic screening programs in Iran for MODY.
• Improved MODY diagnosis facilitates personalized treatment and family genetic counseling.