Clinical and Biochemical Characterization of Fabry Disease Associated <scp> <i>GLA</i> </scp> Gene Variants: Data From a Large Cohort of 469 Thousand Genotyped Subjects of the <scp>UK</scp> Biobank Database

Fabry disease (FD) is a lysosomal storage disease due to genetic variants in the GLA gene located on the X chromosome. Males are hemizygous, while many females are genetic mosaics due to the random inactivation of the X chromosome. While most of the identified variants are deleterious for GLA, in some cases, less rare gene variants have been considered responsible for some FD features. GLA variants were selected from the database of 469 thousand genotyped subjects of the UK Biobank database. Pathogenic variants (ALL_P), variants of uncertain significance (ALL_U), and variants with conflicting interpretations of pathogenicity (ALL_C) were grouped, while p.Asp313Tyr, p.Ala143Thr, p.Ser126Gly, p.Arg118Cys, and p.Asn215Ser were evaluated individually. More than 480 thousand subjects not carrying variants in the GLA gene were used as controls in association studies. Clinical and biochemical phenotypes were extracted from the same database, and a FD phenotype score (FASTEX derived Fabry, FDF score) was derived from the FASTEX prognostic to assess the probability of an FD phenotype score. Pathogenic variants and p.Asn215Ser were associated with FDF score, while all other variants were not associated with any FDF feature. Stratification of patients based on a calculated cardiovascular (CV) risk score demonstrated that patients with nonpathogenic variants within the highest CV risk quartile (> 75th percentile) showed characteristic features of FD, whereas those in the lower risk group (< 75th percentile) showed odds ratios indicating inverse association with FD features. In conclusion, the data from UK Biobank suggest that pathogenic variants are always associated with FD features, while variants of uncertain significance and conflicting interpretation acquire an FD phenotype only in the presence of a high CV risk burden.