Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic

J Clin Med 2021 Aug 12;10(16):3543. doi: 10.3390/jcm10163543.

PMID: 34441839

Petra Reková, Gabriela Dostálová, David Kemlink

Highlights: The findings of this study underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

Abstract

Background: Fabry disease (FD) is a rare X-linked glycosphingolipid metabolic disorder caused by pathogenic variants in the alpha-galactosidase A (GLA) gene, which frequently results in neurological symptoms such as stroke. Multiple screening methods looking for GLA variants in stroke survivors lacked specific phenotypic descriptions, making it impossible to assess the pathogenicity of the variants found.

Methods: The clinical features of GLA variant carriers discovered by a countrywide stroke screening program in the Czech Republic are described in this paper. The study comprised a total of 23 participants with eight distinct GLA variants. A team of FD professionals conducted a comprehensive diagnostic examination.

Results: The study led to the proposal that the G325S mutation be reclassified from late-onset to classical phenotype. R30K is a novel variant that has been categorized as a variant of unknown significance (VUS). A stroke in the posterior circulation with an associated abnormal finding in the CSF fluid was the most common symptom in our FD patients. Furthermore, we discovered that cornea verticillata is commonly seen in classical variants.

Conclusion: The necessity of comprehensive phenotypic description and data sharing in the proper diagnosis of pathogenicity of gene variants discovered by high-risk-population screening programs is highlighted by our findings.

Keywords: Fabry disease, GLA gene variants, data sharing, phenotype, screening programs, stroke