Whole-Exome Sequencing in Undiagnosed Muscular Dystrophies: A High Diagnostic Yield and Novel Insights From Iranian Families.
Whole-exome sequencing achieved a 69.2% diagnostic yield in undiagnosed muscular dystrophies.
Whole-Exome Sequencing in Undiagnosed Muscular Dystrophies: A High Diagnostic Yield and Novel Insights From Iranian Families.
Muscular dystrophies (MDs) are a genetically heterogeneous group of disorders, posing significant diagnostic challenges, especially in populations with high consanguinity.
To identify the genetic basis of nondystrophinopathic MDs in Iranian families with inconclusive prior genetic testing and to evaluate the diagnostic yield and mutational spectrum in this population.
We performed whole-exome sequencing on one affected individual from each of 10 unrelated Iranian families with clinically diagnosed MD.
We identified 13 candidate variants in 10 known MD-associated genes, including DYSF , SGCA , TK2 , MAP3K20 , LMNA , COL6A1 , COL6A2 , ITGA7 , MICU1 , and SGCB .
Among these, seven variants (54%) were novel.
The majority of cases (84.6%) followed an autosomal recessive pattern, consistent with high parental consanguinity (70%).
Notably, a de novo splice-site variant in COL6A2 (c.1053+1G>T) was identified in a sporadic case, confirming an autosomal dominant inheritance.
Whole-exome sequencing is a highly effective diagnostic strategy for genetically heterogeneous MDs, particularly in consanguineous populations.
Our study expands the mutational spectrum of MDs in Iran and provides critical data for genetic counseling, prenatal diagnosis, and future therapeutic development.
The high rate of novel variants underscores the importance of population-specific genomic studies.