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.