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

Kolja Lau, Nurcan Üçeyler, Tereza Cairns, Lora Lorenz, Claudia Sommer, Magnus Schindehütte, Kerstin Amann, Christoph Wanner, Peter Nordbeck, Kolja Lau, Nurcan Üçeyler, Tereza Cairns, Lora Lorenz, Claudia Sommer, Magnus Schindehütte, Kerstin Amann, Christoph Wanner, Peter Nordbeck

Abstract

Background: Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.

Methods: This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.

Results: Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.

Conclusion: These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. 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 FD.

Trial registration: ClinicalTrials.gov NCT03362164.

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

Conflict of interest statement

C.W. and P.N. have received speaker honoraria and grants to the institution from Amicus Therapeutics, Idorsia, Sanofi/Genzyme, Shire/Takeda. N.Ü. has received travel grants and honoraria for lectures from Sanofi Genzyme and Takeda Shire, and research funds from Sanofi Genzyme, Takeda Shire, and Idorsia. C.S. has received speaker honoraria from Amicus Therapeutics and Takeda.

© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Figures

FIGURE 1
FIGURE 1
12‐year follow‐up visit of patient 4. (a) The upper picture shows PAS‐stained glomeruli (20‐fold and 40‐fold microscopic magnification) with inconspicuous findings. Bottom: Electron microscope views (2000‐fold and 5000‐fold magnification) with no signs of Fabry‐specific changes. (b) Cardiac MRI: Short‐axis and long‐axis view (upper two pictures: SSFP; lower two pictures: Late gadolinium enhanced T1‐IR) reveal no signs of cardiac hypertrophy or fibrosis. (c) Brain MRI: The upper pictures show axial and coronal T1‐weighted images and axial and coronal FLAIR images at the level of the basal ganglia, the pulvinar thalami appears isointense to the cortex. The bottom picture of an intracerebral angiography shows no abnormal findings

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