Prevalence of Fabry disease-causing variants in the UK Biobank

J Med Genet. 2023 Apr;60(4):391-396. doi: 10.1136/jmg-2022-108523.

PMID: 35977816

Mark Gilchrist, Francesco Casanova, Jess S Tyrrell

Highlights: The aim of this study is to determine the prevalence of Fabry disease-causing variants in UK Biobank.

Abstract

Background: Fabry disease is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase A enzyme leading to deposition of globotriaosylceramide in multiple organ sites with significant cardiovascular and renal involvement. According to clinical ascertainment, estimates of the prevalence of Fabry disease range from 1 in 40,000 to 1 in 170,000 people worldwide. The goal of this study was to find out how common Fabry disease-causing mutations were in the UK Biobank.

Methods: With the exome sequencing data from 200,643 people from the UK Biobank, GLA gene variations were searched. Pathogenicity is classified according to the ACMG/AMP guidelines (American College of Medical Genetics/Association for Molecular Pathology), and baseline biomarker data, hospital ICD-10 codes, general practitioner records, and self-reported health data with those without pathogenic variants were contrasted.

Results: 81 GLA coding variants were found. On the basis of their rarity (1/10,000 individuals), history of causing Fabry disease, or status as protein-truncating variants, eight potential pathogenic mutations were identified. Thirty-six individuals carried one of these variants. The prevalence of potentially pathogenic Fabry disease-causing variants in the UK Biobank is 1/200,643 for variants causing classic Fabry disease and 1/5732 for variants causing late-onset disease.

Conclusion: GLA variants that cause Fabry disease are more common in an unselected population sample than the reported prevalence of Fabry disease. The majority of these variants had a later onset. It's probable that the prevalence of Fabry disease with later onset is higher than currently thought.

Keywords: Cardiovascular Diseases, Genetics, Nephrology, Screening