<i>D313Y</i> Variant in Fabry Disease: A Systematic Review and Meta-analysis.

Abstract

There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (<i>GLA</i>) gene. Among them, the potential pathogenicity and clinical relevance of <i>D313Y</i> variation in patients with FD remain debated. We performed a systematic review and meta-analysis of studies reporting <i>D313Y</i> as single occurring variant in the <i>GLA</i> gene and sought to evaluate (1) the prevalence of <i>D313Y</i> variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in <i>D313Y</i>-positive patients, and (3) the proportion of <i>D313Y</i>-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). Forty cohorts comprising 211 individuals with <i>D313Y</i> variation among 42,723 participants with available <i>GLA</i> gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of <i>D313Y</i> variation (4.9%, 95% CI 1.6%-9.9%; I² = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I² = 1.9%; <i>p</i> = 0.004). The prevalence of <i>D313Y</i> variation was 0.6% (95% CI 0.3%-1%; I² = 74.1%), 0.4% (95% CI 0.2%-0.7%; I² = 0%), and 0.3% (95% CI 0.2%-0.4%; I² = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. <i>D313Y</i> was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I² = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I² = 34%) and 16.2% (95% CI 8%-26.4%; I² = 35%) of cases, respectively. <i>D313Y</i>-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I² = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I² = 51%) and 28.5% (95% CI 17.8%-40.5%; I² = 61%) of cases, respectively. <i>D313Y</i> variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify <i>D313Y</i>-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.