Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly)

Mol Genet Genomic Med. 2022 May;10(5):e1912. doi: 10.1002/mgg3.1912.

PMID: 35212486

Kolja Lau, Nurcan Üçeyler, Tereza Cairns

Highlights: Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to Fabry disease.

Abstract

Background: Depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA), Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varied organ involvement and symptoms. With the increased availability of genetic testing, it is critical to assess the pathogenicity of each genetic variant to determine whether or not FD-specific medication is required in affected patients and relatives at the time of presentation or in the future.

Methods: This case series examines the clinical impact of the GLA gene mutation c.376A>G (p.Ser126Gly) in five individuals from various families who attended our center between 2009 and 2021 (one heterozygous and one homozygous female, three males). In all patients, comprehensive neurological, nephrological, and cardiac exams were carried out. After 12 years, one patient had a follow-up examination.

Results: Unspecific neurological symptoms were the most common index events that led to the suspicion of FD. However, FD-specific biomarkers, imaging studies (e.g., brain MRI, heart MRI), and tissue-specific diagnostics, such as kidney and skin biopsies, revealed no indication of FD-specific symptoms or organ involvement in all patients. This includes the results of a 12-year follow-up on one patient who had a kidney biopsy.

Conclusion: These data imply that p.Ser126Gly is a benign GLA gene variant that does not cause FD. To separate typical symptoms widely prevalent in the general population from those secondary to FD, a precise clinical evaluation in patients identified with genetic alterations of uncertain relevance should be done.

Keywords: Fabry, diagnosis in Fabry disease, gene variant, genotype/phenotype correlation, lysosomal storage disease