Genome sequencing reveals the prevalence of Fabry disease-causing variants in Japan: Evidence from the Tohoku Medical Megabank.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity and characterized by multisystem involvement. Although considered rare, with reported prevalence ranging from 1 in 40,000 to 1 in 140,000, its true frequency in the general population remains uncertain. We aimed to determine the prevalence of FD-causing variants in a community-based cohort from the Tohoku Medical Megabank, Japan. Methods: Genome sequencing was performed in 68,615 individuals. Variant pathogenicity was classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Baseline demographics, serum α-galactosidase A (GLA) activity, plasma globotriaosylsphingosine, and self-reported health data were assessed. Results: Pathogenic GLA variants were identified in 4 individuals and a likely pathogenic variant in 1 individual (mean age 49.3 ± 15.9 years); all were female, corresponding to a prevalence of 1 in 13,723. All pathogenic variants were c.902G>A, associated with the cardiac phenotype, whereas the likely pathogenic variant was c.1076T>C. Mean plasma GLA activity was 5.64 ± 1.73 mmol/hr/mL in pathogenic variant carriers and 8.36 mmol/hr/mL in the likely pathogenic carrier. Plasma globotriaosylsphingosine levels were 3.7 ± 0.79 ng/mL and 0.96 ng/mL, respectively. Conclusion: Population based genome sequencing data suggest a higher prevalence of FD-causing variants in Japan than previously reported, highlighting potential underdiagnosis of late-onset FD in women.