Sci Rep. 2026 Jul 14. doi: 10.1038/s41598-026-62249-0. Online ahead of print.
ABSTRACT
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and systemic glycosphingolipid accumulation. Diagnosis remains challenging because of the marked clinical heterogeneity and the frequent delay between symptom onset and definitive diagnosis. This multicenter study performed molecular analysis of the GLA gene in 260 high-risk individuals across Spain between 2002 and 2020. Targeted genetic analysis was performed independently of enzymatic or biomarker results to assess diagnostic yield of direct molecular screening approaches. GLA gene variants were identified in 127 participants (48.8%), comprising 35 distinct variants, of which 25 had been previously reported and 10 were novel. The most frequent variants included the previously reported c.713G > A (p.Ser238Asn) and c.937G > T (p.Asp313Tyr), as well as the novel c.370 - 83_370-79del. Among the novel variants classified as pathogenic, two were nonsense variants (c.142G > T, p.Glu48Ter; c.553 A > T, p.Lys185Ter), two were missense variants (c.347G > T, p.Gly116Val; c.581 C > A, p.Thr194Asn), and three were frameshift variants (c.431del, p.Gly144AlafsX21; c.626_629dup, p.Phe211AlafsTer22; c.894_895del, p.Asn298LysfsTer16). In addition, intronic variants (c.370 - 83_370-79del; c.640 - 620_815del, p.Pro214_Asn272del) and one complex rearrangement (g.100660721_100660722ins) were identified. Among patients harbouring GLA variants with clinical involvement, chronic kidney disease was the most prevalent manifestation (51.5%), followed by cardiac (31%), neurological (17%), dermatological (14%), ocular (8%), and digestive involvement (8%). Three patients exhibited the classical phenotype; two carried previously reported variants (c.242G > C, c.1118G > A), and one carried a novel complex rearrangement. Functional interpretation of the identified variants suggested that nonsense and frameshift variants are likely to result in severe loss of α-galactosidase A activity, whereas missense and intronic variants may be associated with partial enzymatic impairment compatible with non-classical Fabry disease phenotypes. These findings support the use of direct genetic screening in high-risk populations to identify both known and novel GLA variants. However, genetic findings alone are insufficient to establish clinical diagnosis or guide treatment decisions. The development of genotype-phenotype registries and longitudinal follow-up is essential to define the clinical relevance of identified variants, particularly those with uncertain or controversial significance.
PMID:42448825 | DOI:10.1038/s41598-026-62249-0