RESUMO
BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase A enzyme leading to accumulation of globotriaosylceramide in multiple organ sites with prominent cardiovascular and renal involvement. Global prevalence estimates of Fabry disease based on clinical ascertainment range from 1 in 40 000 to 1 in 170 000. We aimed to determine the prevalence of Fabry disease-causing variants in UK Biobank. METHODS: We sought GLA gene variants in exome sequencing data from 200 643 individuals from UK Biobank. We used ACMG/AMP guidelines (American College of Medical Genetics/Association for Molecular Pathology) to classify pathogenicity and compared baseline biomarker data, hospital ICD-10 (International Classification of Diseases version-10) codes, general practitioner records and self-reported health data with those without pathogenic variants. RESULTS: We identified 81 GLA coding variants. We identified eight likely pathogenic variants on the basis of being rare (<1/10 000 individuals) and either previously reported to cause Fabry disease, or being protein-truncating variants. Thirty-six individuals carried one of these variants. In the UK Biobank, the prevalence of likely pathogenic Fabry disease-causing variants is 1/5732 for late-onset disease-causing variants and 1/200 643 for variants causing classic Fabry disease. CONCLUSION: Fabry disease-causing GLA variants are more prevalent in an unselected population sample than the reported prevalence of Fabry disease. These are overwhelmingly variants associated with later onset. It is possible the prevalence of later-onset Fabry disease exceeds current estimates.
