Global prevalence of genetic carriers for ARMC5- and KDM1A-associated primary bilateral macronodular adrenal hyperplasia: insights from a large multiethnic genomic database

Abstract

Purpose: To estimate the global prevalence of genetic carriers of primary bilateral macronodular adrenal hyperplasia (PBMAH)-associated variants in ARMC5 and KDM1A using a large genomic database. Methods: We analyzed sequencing data from 807,162 unrelated individuals in gnomAD v4.1. Two prespecified variant-selection strategies were applied. Strict criteria included ARMC5 and KDM1A variants classified as pathogenic/likely pathogenic (P/LP) in ClinVar/LOVD and germline P/LP variants reported in the literature. Liberal criteria included all strict variants plus rare predicted deleterious variants (nonsense, frameshift, loss of start codon and splice-disrupting variants predicted to be deleterious by in silico analysis) and PBMAH-reported somatic ARMC5 variants from the literature as candidate germline susceptibility alleles. Carrier prevalence was estimated by aggregating allele frequencies of qualifying variants overall and by ancestry. Results: For ARMC5, estimated carrier prevalence was 37.5/100,000 under strict criteria and 64.1/100,000 under liberal criteria. Prevalence varied by ancestry, highest in East Asian individuals (strict: 111.4/100,000; liberal: 173.7/100,000) and lowest in Middle Eastern (strict: 0; liberal: 33.0/100,000) and Ashkenazi Jewish groups (strict: 6.8; liberal: 27.0/100,000). For KDM1A, only three variants met strict criteria; liberal criteria yielded an estimated carrier prevalence of 33.8/100,000, highest in Middle Eastern (66.0/100,000) and lowest in Finnish (6.2/100,000). Several variants were enriched in specific ancestries (e.g., ARMC5 p.Arg454Trp in East Asians; ARMC5 p.Arg879Trp and KDM1A p.Arg196AsnfsTer6 in non-Finnish Europeans). Conclusion: Population-scale data suggest PBMAH genetic susceptibility due to ARMC5 and KDM1A variants may be more common than implied by clinical series and differs across ancestries, underscoring the need for improved variant curation and phenotype-linked studies.