Novel GLA mutation in a high-consanguinity region: insights from Fabry disease screening in Turkiye

Aims: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficient α-galactosidase A (α-Gal A) activity, leading to the accumulation of globotriaosylceramide in multiple organ systems. Its early diagnosis remains a challenge, particularly in high-risk populations. This study aimed to determine the prevalence of FD among hemodialysis patients in Eastern and Southeastern Turkiye, regions with a high rate of consanguineous marriages. Methods: Between 2015 and 2019, 613 adult patients undergoing maintenance hemodialysis across five provinces were screened for α-Gal A activity using dried blood spot testing. Patients with reduced enzyme levels underwent confirmatory testing through leukocyte enzyme assays and GLA gene sequencing. Results: Reduced α-Gal A activity was identified in 15.7% of patients. Genetic analysis in 58 individuals revealed no mutations in males. However, two unrelated female patients were found to carry the same GLA gene variant, c.116C>A (p.T39K), which has not been previously reported in gnomAD or ClinVar databases. The overall prevalence of genetically confirmed FD in this cohort was 0.32%. Conclusion: This is the first regional screening study of FD in Eastern and Southeastern Turkiye. The identification of a novel GLA mutation in a high-consanguinity population underscores the importance of genetic screening in dialysis patients and highlights the need for region-specific diagnostic and counseling strategies.