Medicina (Kaunas). 2026 Jul 12;62(7):1343. doi: 10.3390/medicina62071343.
ABSTRACT
Background and Objectives: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic GLA gene variants, leading to progressive multi-organ damage including end-stage renal disease. Although dialysis patients represent a high-risk population for undiagnosed FD, data from Türkiye using genetic analysis as the primary screening method remain limited. This study aimed to determine FD prevalence among hemodialysis patients across multiple centers in Türkiye and to perform cascade family screening of confirmed cases. Materials and Methods: This multicenter cross-sectional study screened 1359 adult hemodialysis patients across 8 centers in Ankara, Türkiye, using complete GLA gene sequencing. Variants were classified per American College of Medical Genetics and Genomics criteria. Patients with pathogenic variants underwent confirmatory biochemical testing (α-galactosidase A activity and plasma lyso-Gb3). Cascade screening was performed for confirmed index cases. Results: Among 1359 patients (mean age 62.3 ± 14.3 years; 38.5% female), GLA variants were identified in 12 (0.88%): 8 benign/likely benign (including 7 p.D313Y pseudodeficiency alleles), 2 unclassified variants, 1 variant of uncertain significance, and 1 confirmed classic FD (prevalence: 0.07%; 95% CI: 0.002-0.41%). Cascade screening of the index patient identified 6 carriers among 10 relatives tested (60% yield). Three of 7 carriers (43%) were initiated on enzyme replacement therapy. Conclusions: Among 1359 hemodialysis patients, GLA gene sequencing identified 12 variants (0.88%), yet only one was confirmed as a disease-causing mutation responsible for end-stage renal disease (prevalence: 0.07%). The remaining variants comprised polymorphisms, likely benign pseudodeficiency alleles and variants of uncertain significance; most of which would not have been detected by enzyme-based screening alone, as enzyme activity was normal in these carriers. Cascade screening of the single confirmed index case yielded 6 carriers among 10 relatives tested (60%), including one hemizygous male with classic FD on hemodialysis, and three carriers were initiated on enzyme replacement therapy. These findings demonstrate that GLA gene analysis is a valuable instrument for screening in dialysis populations, as it captures the full variant spectrum while enabling rigorous distinction between the overall GLA variant carrier rate and the true disease prevalence defined by variants causing end-stage renal disease. Future screening studies should report prevalence based exclusively on confirmed disease-causing variants rather than total variant counts, which have inflated prevalence estimates in prior literature.
PMID:42512885 | PMC:PMC13414392 | DOI:10.3390/medicina62071343