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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-05-01
|
| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.1912 |
| _version_ | 1818278537822470144 |
|---|---|
| author | Kolja Lau Nurcan Üçeyler Tereza Cairns Lora Lorenz Claudia Sommer Magnus Schindehütte Kerstin Amann Christoph Wanner Peter Nordbeck |
| author_facet | Kolja Lau Nurcan Üçeyler Tereza Cairns Lora Lorenz Claudia Sommer Magnus Schindehütte Kerstin Amann Christoph Wanner Peter Nordbeck |
| author_sort | Kolja Lau |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T23:19:01Z |
| format | Article |
| id | doaj.art-4bf497b4606a453ab46695091b99220e |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-12-12T23:19:01Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-4bf497b4606a453ab46695091b99220e2022-12-22T00:08:21ZengWileyMolecular Genetics & Genomic Medicine2324-92692022-05-01105n/an/a10.1002/mgg3.1912Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly)Kolja Lau0Nurcan Üçeyler1Tereza Cairns2Lora Lorenz3Claudia Sommer4Magnus Schindehütte5Kerstin Amann6Christoph Wanner7Peter Nordbeck8Department of Internal Medicine I University Hospital Würzburg Würzburg GermanyFabry Center for Interdisciplinary Therapy (FAZiT) University Hospital Würzburg Würzburg GermanyDepartment of Internal Medicine I University Hospital Würzburg Würzburg GermanyDepartment of Internal Medicine I University Hospital Würzburg Würzburg GermanyFabry Center for Interdisciplinary Therapy (FAZiT) University Hospital Würzburg Würzburg GermanyDepartment of Diagnostic and Interventional Neuroradiology University Hospital Würzburg Würzburg GermanyDepartment of Nephropathology, Department of Pathology University of Erlangen‐Nürnberg Erlangen GermanyDepartment of Internal Medicine I University Hospital Würzburg Würzburg GermanyDepartment of Internal Medicine I University Hospital Würzburg Würzburg GermanyAbstract 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.https://doi.org/10.1002/mgg3.1912diagnosis in Fabry diseaseFabry diseasegene variantgenotype/phenotype correlationlysosomal storage disease |
| spellingShingle | Kolja Lau Nurcan Üçeyler Tereza Cairns Lora Lorenz Claudia Sommer Magnus Schindehütte Kerstin Amann Christoph Wanner Peter Nordbeck Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) Molecular Genetics & Genomic Medicine diagnosis in Fabry disease Fabry disease gene variant genotype/phenotype correlation lysosomal storage disease |
| title | Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) |
| title_full | Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) |
| title_fullStr | Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) |
| title_full_unstemmed | Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) |
| title_short | Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376A>G (p.Ser126Gly) |
| title_sort | gene variants of unknown significance in fabry disease clinical characteristics of c 376a g p ser126gly |
| topic | diagnosis in Fabry disease Fabry disease gene variant genotype/phenotype correlation lysosomal storage disease |
| url | https://doi.org/10.1002/mgg3.1912 |
| work_keys_str_mv | AT koljalau genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT nurcanuceyler genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT terezacairns genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT loralorenz genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT claudiasommer genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT magnusschindehutte genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT kerstinamann genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT christophwanner genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly AT peternordbeck genevariantsofunknownsignificanceinfabrydiseaseclinicalcharacteristicsofc376agpser126gly |