Fabry disease (FD) is a rare, progressive, inherited disorder resulting from a markedly deficient enzyme activity of α-galactosidase A (AGAL), which is caused by mutations in the X-linked α-galactosidase A (GLA) gene. FD is perceived as a multidomain or a heterogeneous disease phenotype associated with complex pathophysiological manifestations and cascading pathways. The AGAL activity accurately predicts the severity of FD. It is vital to study the variants related to FD in the Gulf region because the existing population is mixed, and a founder gene, if predominant in any generation, leads to greater birth rates of autosomal recessive disorders. Identifying the pathogenicity of GLA mutations plays a crucial role in diagnosing and treating FD. We conducted an extensive review of the literature. We pooled data from randomized controlled trials, retrospective observational trials, systematic reviews, and case reports on p.D313Y variant pathogenicity versus nonpathogenicity and clinical significance for establishing genotype-phenotype correlations in patients with suspected FD. Overall, in our review analysis, we included 25 studies. Data on study participants, type of mutation, clinical manifestations, and clinical relevance were collected. Interestingly, we found strong evidence reporting nonpathogenicity of the D313Y variant and categorized it as benign or a variant of uncertain significance. These results will facilitate the clinicians to decide on the correct diagnosis and treatment of FD. Further research is warranted, which would help clarify a possible relationship between the variant and clinical manifestations.
Key words: Fabry disease, p.D313Y, α-galactosidase A, GLA variants, pathogenic variants, variant of unknown significance
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