Exome Sequencing Reveals Novel Variants in Genetic Skeletal Disorders: Insights From a Cohort in Southwest Iran

Genetic skeletal disorders (GSDs) comprise a diverse group of disorders that affect bone development and homeostasis. In some areas of Iran, GSD occurs more frequently than in other places for still unknown reasons. The aim of this study was to characterize the genetic landscape of GSDs in a cohort from southwestern Iran using Exome sequencing (ES), with a focus on identifying pathogenic and likely pathogenic variants. Osteogenesis Imperfecta (OI) was the most prevalent disorder, with an unexpectedly high frequency of autosomal recessive subtypes, likely due to a high consanguinity rate (61.3%) in the cohort. Achondroplasia (ACH) was the second most common disease and, comparable to another population, the NM_000142.5:c.1138G>A, p.(Gly380Arg), was the most common variant in FGFR3. ES identified twenty novel and fifteen previously reported pathogenic variants in several genes associated with GSDs. We provide the first comprehensive ES-based molecular diagnosis of GSDs in an Iranian population and uncover novel pathogenic variants that expand the known spectrum of variants. The results underscore the importance of genetic testing in the diagnosis of rare skeletal diseases and highlight the need for targeted genetic counseling in populations with high consanguinity.