Enrichment of Rare mtDNA 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 (GU₅80) and renal failure (GU₅82). 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 (GU₅82. 2;OR=1. 55) and renal failure (GU₅82; OR=1. 53). Among undiagnosed carriers, genotypephenotype review identified concordant manifestations in 14%, including mitochondrial chronic J o u r n a l P r e -p r o o f 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-renalassociated 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.