Analysis of whole-exome sequencing data from nearly 10,000 Iranian individuals: identification of recessive mitochondrial disease variants and proposal of a population-specific carrier screening panel

Abstract

BACKGROUND: Mitochondrial diseases, often stemming from recessive nuclear gene mutations, represent a heterogeneous group of disorders with significant morbidity and mortality. Carrier screening for these conditions is population-specific, yet data on the pathogenic variant burden in the Iranian population remain limited. This study aimed to analyze whole-exome sequencing (WES) data from 9989 Iranian individuals to identify the spectrum and frequency of recessive mitochondrial disease variants and to develop a population-specific carrier screening panel. METHODS: We analyzed WES data from 9989 unrelated Iranian individuals. Variants in 1,564 nuclear genes associated with mitochondrial function were filtered for rarity (minor allele frequency < 0.01 in public databases), predicted pathogenicity, and recessive inheritance patterns (homozygous or compound heterozygous). Clinically relevant variants were manually curated, and carrier frequencies for significant recessive mitochondrial conditions were calculated. RESULTS: Our analysis identified variants across 15 groups of mitochondrial-related nuclear genes in 345 individuals recognized as carriers. Of these, 123 variants (35.6) were classified as Pathogenic, and 154 variants (44.6) were classified as Likely Pathogenic according to ACMG guidelines. CONCLUSIONS: This study provides the first large-scale WES-derived assessment of recessive mitochondrial disease carrier burden in the Iranian population. The high estimated carrier rate supports implementing population-specific preconception screening. The results of this study can be used for design of targeted panels of nuclear mitochondrial genes to identify at-risk couples, facilitating genetic counseling and reproductive decision-making in Iran.