Population-based estimates of the global prevalence and carrier frequency of apparent mineralocorticoid excess caused by 11β-hydroxysteroid dehydrogenase type 2 deficiency

Abstract

Background: Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disorder caused by biallelic inactivating variants in the HSD11B2 gene resulting in hypertension and electrolyte abnormalities due to cortisol-mediated activation of mineralocorticoid receptors. We aimed to utilize data from a large genomic database to estimate the prevalence and carrier frequency of AME, with stratification by ethnic ancestry to identify potential disparities. Methods: We analyzed sequencing data from 807,162 unrelated individuals in the gnomAD v4.1 database, representing diverse ethnic ancestries. Potentially disease-causing HSD11B2 variants were identified using three approaches: classification as pathogenic/likely pathogenic (P/LP) in ClinVar, association with AME based on systematic review of the literature, or predicted deleterious effects by in silico tools. Carrier frequency was calculated based on combined allele frequencies. Disease prevalence was estimated using Hardy-Weinberg equilibrium assumptions. Analyses were stratified by ancestry and variant selection criteria. Results: Of 1,506 HSD11B2 variants in gnomAD, 160 qualified as potentially pathogenic. Using strict criteria (ClinVar/literature), the global carrier frequency was 24.5/100,000 individuals and disease prevalence was 0.6/10,000,000. With liberal criteria (including in silico predictions), these increased to 82.6/100,000 and 6.8/10,000,000. The highest carrier frequencies were observed in Middle Eastern individuals (132.0/100,000 under strict criteria) and South Asians (147.1/100,000 under liberal criteria). Several variants were enriched in specific populations. Conclusion: This study provides the first global, ancestry-stratified estimates of AME carrier frequency and prevalence, revealing variability by ancestry and variant classification. Results highlight the need for improved variant curation and broader population representation in genomic research.