Enrichment of Rare Mitochondrial DNA Variants Among Individuals With Kidney Disease Reveals Undiagnosed Mitochondrial Disease

Introduction Pathogenic mitochondrial DNA (mtDNA) variants cause multisystem disease, yet their contribution to kidney disease remains incompletely characterized, partly due to exclusion of the mitochondrial genome from genetic studies. Methods We evaluated mtDNA variation in 27,747 participants from the Mount Sinai Million Health Discoveries Program (MSM), an ancestrally diverse biobank with whole-exome sequencing (WES) and linked electronic health records (EHR). mtDNA variants were identified using MitoVerse and classified with MITOMAP. Kidney disease was defined using renal PheCodes for glomerular disease (GU_580) and renal failure (GU_582). Prior mitochondrial diagnoses were ascertained from EHR to identify undiagnosed individuals. Associations were adjusted for age, sex, and ancestry, with genotype–phenotype review. Results Among 3,935 individuals with kidney disease, 45 carried clinically associated mtDNA variants, 42 of whom had no prior clinical mitochondrial diagnosis. mtDNA variants were enriched among individuals with kidney disease and associated with increased odds of renal involvement (OR=1.72). Associations were strongest for chronic kidney disease (GU_582.2; OR=1.55) and renal failure (GU_582; OR=1.53). Among undiagnosed carriers, genotype–phenotype review identified concordant manifestations in 14%, including mitochondrial chronic kidney disease with hyperuricemia. Variant-level analysis identified enrichment of m.1630A>G in MT-TV (OR=5.56), with additional variants showing trends. Both renal- and non–renal-associated pathogenic mtDNA variants were observed. Conclusion Pathogenic mtDNA variants are overrepresented among individuals with kidney disease, often without a known mitochondrial diagnosis. These findings support a contributory role for mtDNA in renal disease and highlight the value of mtDNA analysis into kidney disease research and clinical evaluation, particularly for identifying unrecognized mitochondrial disease with renal involvement.