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Inherited metabolic disorder-related genes and mutation spectrum in Iranians: an 11-year analysis using next-generation sequencing and sanger sequencing

Parnian Alagha Negar Molaei M. Beheshtian F. Ahangari Shima Dehdahsi M. Fadaee M. Ashki Zhila Ghaderi Zohreh Elahi Raheleh Vazehan Maryam Mozaffarpour Nouri Parishad Saei Khadijeh Noudehi Fatemeh Fatehi Shima Zamanian Najafabadi Fariba Afroozan Banafsheh Salmani Mahdieh Kooshki Armita Ghaderi Z. Vahidi Mina Makvand A. Ahmadpour Mahsa Tahmasebivand Elmira Shiuokhi Saeed Talebi R. Badv Babak Zamani Farhad Mahvelati-Shamsabadi Bahram Haghi Ashtiani Payam Sarraf Haleh Habibi Afshin Fayyazi A. Okhovat Mahmoudreza Ashrafi F. Fatehi P. Karimzadeh S. Nafissi K. Kahrizi A. Kariminejad H. Najmabadi

Oct 2026 · Orphanet Journal of Rare Diseases · 0 citations

Abstract

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare diseases caused by genetic variants that disrupt key metabolic pathways. This retrospective study primarily aimed to characterize the molecular and genetic spectrum of IMD-related genes and assess the diagnostic yield of next-generation sequencing (NGS) among 405 individuals clinically suspected of having IMDs. We also evaluated 315 individuals with non-IMD clinical suspicion who were found to carry IMD-related gene variants through NGS and 300 individuals referred for Sanger sequencing of IMD-related genes. The diagnostic yield for individuals suspected of having IMDs was 46%, with TYR , ETFDH , and AGL being the most frequently mutated genes. Among individuals with non-IMD suspicion initially, SPG11 , CHRNE , GNE , and PLA2G6 were most prevalent. The most prevalent Human Phenotype Ontology (HPO) disorders included abnormalities of the nervous system and musculature abnormalities. Potentially treatable genes were observed in 38% of individuals with IMD-related genes, with GNE , ETFDH , AGL , GAA , and GALC being the most frequent. In the Sanger cohort, PAH , ATP7B , and AGXT were the most frequently requested genes. 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 clinical application. These findings have important implications for genetic counseling and early diagnosis, particularly in consanguineous populations. Furthermore, considering treatable genes in this study could be valuable for inclusion in national screening panels and improve early clinical management.

DOI Semantic Scholar

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