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

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.

Genetic variants of unknown significance in alpha‐galactosidase A: Cellular delineation from Fabry disease

“…No FD manifestation and normal leukocyte GLA activity were observed in clinical tests of men carrying the p.S126G variant as was also described before 35,36 . Similarly, we found normal GLA activity without Gb3 deposits in all of our in vitro models which adds to evidence of the benign nature of p.S126G by the absence of pathological changes 29 …”

“…No FD manifestation and normal leukocyte GLA activity were observed in clinical tests of men carrying the p.S126G variant as was also described before. 35,36 Similarly, we found normal GLA activity without Gb3 deposits in all of our in vitro models which adds to evidence of the benign nature of p.S126G by the absence of pathological changes. 29 When considering the 3D structure of GLA, the amino acid exchange of the investigated VUS was located towards the protein surface and did not intersect with the binding or active site of the enzyme (Figure 6).…”

In vitro characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease

“…S126G (p.Ser126Gly, c.376 A > G) with a population frequency of 0.06% [ 11 ] is such a genetic variant considered “benign” and a VUS [ 37 ]. While in one study, end-stage renal disease was described in two patients [ 72 ], other studies did not show a pathogenic nature of S126G [ 15 , 39 , 51 ]. Since previous data was mostly acquired by clinical assessment of patients and enzyme activity measurements [ 2 , 15 , 39 ], basic science approaches on cellular level, going beyond the established measures, can help to answer the question of pathogenicity and strengthen patients` confidence in medical decisions.…”

“…While in one study, end-stage renal disease was described in two patients [ 72 ], other studies did not show a pathogenic nature of S126G [ 15 , 39 , 51 ]. Since previous data was mostly acquired by clinical assessment of patients and enzyme activity measurements [ 2 , 15 , 39 ], basic science approaches on cellular level, going beyond the established measures, can help to answer the question of pathogenicity and strengthen patients` confidence in medical decisions. Here, we present data on the GLA variant S126G, linking thorough clinical examination with a patient-derived in vitro system to investigate morphology and functionality of skin cells, induced pluripotent stem cells (iPSC), and sensory neurons.…”