ENOrphanet Journal of Rare Diseases | Global Carrier Frequency and Prevalence of HSD11B2 Variants
Date: April 05, 2025
Classification: Frontiers
Recommend:
This study provides the first population-based carrier frequency and prevalence estimates of Apparent Mineralocorticoid Excess (AME) caused by HSD11B2 variants using the large-scale gnomAD v4.1 genomic database, highlighting the impact of genetic ancestry and variant classification criteria on disease burden estimation. It offers crucial reference for future functional studies and clinical screening.
Literature Overview
This article, titled 'Population-based estimates of the global prevalence and carrier frequency of apparent mineralocorticoid excess caused by 11β-hydroxysteroid dehydrogenase type 2 deficiency', published in the Orphanet Journal of Rare Diseases, reviews and summarizes the global distribution of HSD11B2 variants associated with Apparent Mineralocorticoid Excess (AME). It estimates carrier frequency and disease prevalence across different populations by integrating ClinVar, literature, and in silico prediction tools. The article further highlights the limitations of current variant classification systems and emphasizes the need for more population-representative genomic studies. Additionally, it reveals the enrichment of specific variants in certain ancestral populations, suggesting potential ancestry-specific differences in genetic epidemiology.Background Knowledge
Apparent Mineralocorticoid Excess (AME) is a rare autosomal recessive disorder caused by mutations in the HSD11B2 gene. The disease mechanism involves the failure of cortisol to be converted into cortisone, leading to abnormal activation of the mineralocorticoid receptor, which results in hypertension, hypokalemia, and renal dysfunction. It typically manifests in childhood with symptoms such as severe hypertension, nephrocalcinosis, and hypokalemic paralysis, but epidemiological data are scarce due to its rarity. Currently, studies on AME-related genetic variants mainly rely on small case reports or family studies, lacking large-scale, population-representative genomic data. This study presents the first systematic assessment of global carrier frequency and disease prevalence of HSD11B2 variants associated with AME using the gnomAD v4.1 database (over 800,000 individuals). It integrates ClinVar, literature, and in silico tools for variant classification and calculates population-specific prevalence using Hardy-Weinberg equilibrium. The results indicate that different variant selection criteria significantly affect carrier frequency and prevalence estimates, and that Middle Eastern and South Asian populations exhibit higher carrier rates than the global average. The study also highlights the current limitations of ClinVar classification, noting that experimental validation is required for some variants to improve the accuracy of genetic diagnosis. This research provides a critical foundation for future genetic screening and functional studies.
Research Methods and Experiments
The research team analyzed HSD11B2 gene sequencing data from 807,162 unrelated individuals in the gnomAD v4.1 database to identify potentially pathogenic variants. Classification criteria included variants already classified as pathogenic or likely pathogenic (P/LP) in ClinVar, AME-related variants reported in the literature, and harmful variants predicted by in silico tools such as CADD, SIFT-indel, SpliceAI, and REVEL. Carrier frequency was calculated based on allele frequency, and disease prevalence was estimated using Hardy-Weinberg equilibrium. The analysis was stratified by ancestral populations, including African, Admixed American, East Asian, Middle Eastern, and South Asian groups, to reveal potential genetic epidemiological differences.Key Findings and Perspectives
Significance and Future Directions
This study provides the first large-scale, population-based genomic data for global epidemiological analysis of AME, offering valuable insights for optimizing clinical screening strategies and improving genetic diagnostic standards. Future research should integrate phenotypic data to further validate the pathogenicity of VUS variants and expand the representation of non-European populations in genomic databases to enhance the comprehensiveness and accuracy of genetic assessments.
Conclusion
This study, using the gnomAD v4.1 database, presents the first estimates of global carrier frequency and disease prevalence of HSD11B2 variants associated with Apparent Mineralocorticoid Excess (AME). The research identifies significant differences in carrier frequency among ancestral populations, particularly higher rates in Middle Eastern and South Asian groups, suggesting potential genetic enrichment. Different variant selection criteria (strict vs. relaxed) significantly affect disease burden estimation, highlighting the limitations of current pathogenicity classification systems. The study also notes that while the gnomAD database provides valuable resources for large-scale population genomic analysis, the sample sizes for certain populations (e.g., Middle Eastern and Ashkenazi Jewish) remain limited, which may affect the accuracy of estimates. Additionally, the lack of phenotypic data restricts genotype-phenotype correlation analysis. Future studies should integrate multi-omics data and experimental validation to improve pathogenicity classification of HSD11B2 variants and enhance the reliability of genetic screening and diagnosis. This study establishes a critical foundation for the genetic epidemiology of AME and underscores the importance of population diversity in global genomic research.
