MO042PREVALENCE OF FABRY DISEASE CAUSING VARIANTS IN THE UK BIOBANK. (29th May 2021)

• Record Type: Journal Article
• Authors: Gilchrist, Mark; Casanova, Francesco; Tyrrell, Jessica; Fife, Nicole; Young, Katie; Oram, Richard; Weedon, Michael
• Is Part Of: Nephrology dialysis transplantation. Volume 36(2021)Supplement 1
• Publication Date: 2021-05-29
• Subjects: Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfab080.0014
• Languages: English
• ISSNs: 0931-0509

Abstract

Abstract: Background and Aims: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from deficiency of the alpha-galactosidase A enzyme. This leads to the accumulation of globotriaosylceramide in multiple organ sites with prominent renal involvement, cardio and cerebrovascular disease, as well as neurological, dermatological, and gastrointestinal pathology in affected individuals. Clinical manifestations are highly heterogeneous with considerable variation depending on the specific variant and even within families with the same variant. Prevalence estimates from studies of case control cohorts range from 1 in 40, 000 to 1 in 140, 000. We sought to determine the prevalence of Fabry disease causing mutations in an unbiased adult population sample using the UK Biobank. Method: UK Biobank comprises approximately 500, 000 participants with extensive phenotyping and genetic data linked to clinical care records. Exome sequencing data from 200643 individuals from the UK Biobank were examined for variants in the GLA gene. Likely mutations were searched for in ClinVar and HGMD with subsequent review of supporting literature. We used ACMG guidelines to classify the pathogenicity of variants. Results: Eighty one coding variants were identified in GLA. Nine of these variants were rare (<1 in 10, 000 individuals) and either protein truncating variants or previously reported to cause Fabry's disease. Thirty seven individuals, (14 males, 22 females, 1 missing data) carried one of these GLA variants. The most common variant was the cardiac predominant phenotype causing N215S variant (18/37). 6/37 had the R363C variant, 4/37 had R356Q. The R112H, R301Q, I198T variants were each identified in 2 individuals. There were single individuals with I232T, K240fs, and E66G variants. Two male individuals (with I232T, K240fs variants) had HES codes compatible with a known diagnosis of Fabry disease. The remaining 12/14 males did not have evidence of an existing diagnosis of Fabry disease. No female participants had HES codes indicating an existing diagnosis of Fabry disease. The overall prevalence of Fabry disease causing variants in the UK Biobank is 1 in 5, 422. The N215 variant alone has a prevalence of 1 in 11, 147. Conclusion: Reported Fabry disease causing GLA variants are far more prevalent in an unselected population sample than would be expected from the reported prevalence of Fabry disease. This may be because some of the reported variants are not pathogenic, or are predominantly later-onset causing variants with reduced penetrance. The true prevalence of Fabry disease may be substantially higher than current estimates.