Estimated global prevalence of genetic carriers of hereditary pheochromocytoma-paraganglioma syndrome in a large multiethnic genomic database.

Objectives: To estimate the global prevalence of genetic carriers of pheochromocytoma-paraganglioma syndromes (PPGLs) in a large multiethnic genomic database.

Methods: We analyzed sequencing data from 807 162 unrelated individuals in the gnomAD v4.1 database, representing a global population of diverse ethnic ancestries. Eleven PPGLs-associated genes were examined: FH, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL, and MAX. Pathogenic or likely pathogenic variants (P/LP) were identified from ClinVar, while additional predicted deleterious variants were included based on loss-of-function annotations and splice prediction in silico tools. Prevalence estimates of genetic carriers were calculated by combining allele frequencies of qualifying variants.

Results: The prevalence of SDHA carriers was the highest when aggregating allele frequencies of both ClinVar P/LP and predicted deleterious variants (158.83 per 100 000), followed by NF1 (93.66 per 100 000) and FH (72.23 per 100 000), while VHL and MAX had the lowest prevalence. Substantial variation was observed across ancestries, with certain variants enriched in specific populations (eg, SDHC p.Tyr126Cys in non-Finnish Europeans; FH c.556-4A > G in East Asians). Carriers of SDHB, SDHC, and TMEM127 ClinVar P/LP or predicted deleterious variants were absent in the Middle Eastern group; SDHAF2 and SDHC were absent in the Ashkenazi Jewish group; and SDHAF2 and TMEM127 were absent in the Finnish group. Predicted deleterious variants significantly increased carrier estimates for SDHAF2, SDHD, and TMEM127.

Conclusion: Our study highlights the variability in PPGL-associated mutation carrier prevalence across genes and ancestries. The findings underscore potential disparities in genetic risk that may not have been fully captured by clinical cohorts.