Inherited Metabolic Disorder-Related Genes and Mutation Spectrum in Iranians: An 11-Year Analysis Using Next-Generation Sequencing and Sanger Sequencing

Background Inherited metabolic disorders (IMDs) are a heterogeneous group of rare diseases caused by genetic variants that disrupt key metabolic pathways. This retrospective study aims to provide a comprehensive molecular understanding of IMDs in Iran by studying the genetic profiles of individuals clinically suspected of IMDs (n = 405) referred to our center, along with individuals (n = 315) with non-IMD suspicion but with variants identified in IMD-related genes from our NGS cohort, and 300 individuals referred for Sanger sequencing of IMD-associated genes. Results The diagnostic yield for individuals suspected of having IMDs was 46% and the most frequently mutated genes were TYR, ETFDH , and AGL . Among individuals with non-IMD suspicion initially, the most prevalent genes were SPG11 , CHRNE , GNE , and PLA2G6 . The most prevalent Human Phenotype Ontology (HPO) disorders included abnormal central motor function, musculature abnormalities, and nervous system abnormalities. Suggestive treatable genes were observed in 38% of our individuals with IMD-related genes. The most commonly identified treatable genes were GNE , ETFDH , AGL , GAA , and GALC . Within the Sanger sequencing cohort, PAH , ATP7B , and AGXT were the most frequently requested genes. Conclusions This study offers valuable insights into the genetic spectrum of IMDs in Iran, highlighting frequently mutated genes across different IMDs groups and potential targets for further research or clinical application. These findings have important implications for genetic counseling and early interventions, particularly in consanguineous populations. Furthermore, consideration of treatable genes in this study could be valuable for inclusion in national screening panels and improving early diagnosis and clinical management.