Abstract
INTRODUCTION: Fabry disease is an X-linked disorder that results from pathogenic GLA variants and can now be treated. Most studies of its population frequency have examined only males or attendees at kidney failure or cardiac clinics. This study determined the prevalence of undiagnosed Fabry disease from predicted pathogenic GLA variants in the general population. METHODS: The Genome Aggregation Database (gnomAD) was examined for predicted pathogenic GLA variants based on variant rarity (≤5), and transcript effect in 4 computational tools (CADD >20, PP2 >0.95, SIFT <0.05, Mutation Taster - Disease-causing) and amino acid conservation in vertebrates in a Clustal. RESULTS: Predicted pathogenic variants in GLA occurred in 1 in 3225 of the gnomAD population and 1 in 3478 of its control subset. Predicted pathogenic variants were more common in women than expected (3.1:1), which is consistent with men being excluded from gnomAD because of Fabry complications. Predicted pathogenic variants were not found in members of this cohort with South Asian, Ashkenazim, or Finnish ancestries. Variants identified as pathogenic in the Fabry database were found in 1 in 2651 individuals of the gnomAD database and pathogenic variants from ClinVar in 1 in 4420. DISCUSSION: The population frequency of 1 in 3225 for undiagnosed men and women with Fabry disease still represents an underestimate because our pathogenicity criteria were rigorous, the cohort did not include already-diagnosed individuals, and whole exome sequencing does not detect intronic variants and large deletions. This study confirms that Fabry disease is more common than previously recognized and still underdiagnosed especially in women.