Novel GLA Variants: 10 Experts’ Tips for the Clinical Assessment of Fabry Disease
12 affiliations
- 1Nephrology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
- 2School of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
- 3Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
- 4Nephrology Department, IRCCS S. Orsola Hospital, 40138 Bologna, Italy
- 5Nephrology, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- 6Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
- 7Nephrology, Dialysis and Transplant Unit, Department of Medicine, Padova University Hospital, 35128 Padova, Italy
- 8Department of Medical and Cardiovascular Sciences, La Sapienza University of Rome, 00185 Rome, Italy
- 9Department of Public Health, Federico II University of Naples, 80138 Naples, Italy
- 10Department of Pediatrics, University of Turin, 10124 Torino, Italy
- 11Laboratory of Molecular Genetics of Neurometabolic Diseases, Department of Neuroscience and Human Genetics, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy
- 12Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, 50139 Florence, Italy
Abstract
The increasing use of next-generation sequencing (NGS), including multigene panels and exome and genome sequencing, has led to increased identification of rare and previously unreported variants in Mendelian disorders, though evidence supporting their clinical interpretation remains limited. In Fabry disease (FD), this issue is particularly relevant because the interpretation of individual GLA gene variants contributes to establishing whether a variant supports the diagnosis, with an impact on treatment decisions. In fact, FD is characterized by a phenotypic heterogeneity depending on patients’ biological sex and the underlying GLA variant. This represents the main reason why integrating genetic data with phenotypic expression is challenging, and defining the pathogenic role of novel variants remains complex. Early discrimination between pathogenic and non-pathogenic GLA variants is essential. However, variant classification, a definitive diagnosis of FD, and the decision to start disease-specific treatment are separate steps. A variant of uncertain significance (VUS), an isolated biochemical abnormality or non-specific organ involvement, is not in itself sufficient to establish the diagnosis or justify enzyme replacement or chaperone therapy. In fact, the most severe cases of FD have a significantly compromised quality of life up to reduced life expectancy, especially with regard to cardiac and renal complications. In recent years, some GLA variants have been reclassified following investigation and clinical observations by multidisciplinary working groups, making it possible to better define if they are pathogenic or not. Regardless of the clinical scenario leading to the identification of a novel GLA variant (i.e., family screening, neonatal screening, clinical profile suggestive of FD, incidental finding), any genetic finding becomes relevant when it is complemented by laboratory, clinical and instrumental investigations that require a concerted effort among the many health care professionals involved in the diagnostic process. The present work summarizes the outcomes of a series of expert meetings with the aim to provide some shared and practical indications for managing the genetic report of a novel GLA variant in order to promptly start the most suitable diagnostic journey and assess corresponding phenotype and clinical characterization.
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BibTeX
@article{pieruzzi2026novel,
title = {{Novel GLA Variants: 10 Experts’ Tips for the Clinical Assessment of Fabry Disease}},
author = {Federico Pieruzzi and Renzo Mignani and Sandro Feriozzi and Marialuisa Zedde and Gianni Carraro and Cristina Chimenti and Antonio Pisani and Marco Spada and Amelia Morrone},
journal = {Journal of clinical medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15197655},
url = {https://europepmc.org/article/PMC/PMC13666460},
note = {CC BY},
}
RIS
TY - JOUR
TI - Novel GLA Variants: 10 Experts’ Tips for the Clinical Assessment of Fabry Disease
AU - Federico Pieruzzi
AU - Renzo Mignani
AU - Sandro Feriozzi
AU - Marialuisa Zedde
AU - Gianni Carraro
AU - Cristina Chimenti
AU - Antonio Pisani
AU - Marco Spada
AU - Amelia Morrone
PY - 2026
DA - 2026/10/01
JO - Journal of clinical medicine
DO - 10.3390/jcm15197655
UR - https://europepmc.org/article/PMC/PMC13666460
AB - The increasing use of next-generation sequencing (NGS), including multigene panels and exome and genome sequencing, has led to increased identification of rare and previously unreported variants in Mendelian disorders, though evidence supporting their clinical interpretation remains limited. In Fabry disease (FD), this issue is particularly relevant because the interpretation of individual GLA gene variants contributes to establishing whether a variant supports the diagnosis, with an impact on treatment decisions. In fact, FD is characterized by a phenotypic heterogeneity depending on patients’ biological sex and the underlying GLA variant. This represents the main reason why integrating genetic data with phenotypic expression is challenging, and defining the pathogenic role of novel variants remains complex. Early discrimination between pathogenic and non-pathogenic GLA variants is essential. However, variant classification, a definitive diagnosis of FD, and the decision to start disease-specific treatment are separate steps. A variant of uncertain significance (VUS), an isolated biochemical abnormality or non-specific organ involvement, is not in itself sufficient to establish the diagnosis or justify enzyme replacement or chaperone therapy. In fact, the most severe cases of FD have a significantly compromised quality of life up to reduced life expectancy, especially with regard to cardiac and renal complications. In recent years, some GLA variants have been reclassified following investigation and clinical observations by multidisciplinary working groups, making it possible to better define if they are pathogenic or not. Regardless of the clinical scenario leading to the identification of a novel GLA variant (i.e., family screening, neonatal screening, clinical profile suggestive of FD, incidental finding), any genetic finding becomes relevant when it is complemented by laboratory, clinical and instrumental investigations that require a concerted effort among the many health care professionals involved in the diagnostic process. The present work summarizes the outcomes of a series of expert meetings with the aim to provide some shared and practical indications for managing the genetic report of a novel GLA variant in order to promptly start the most suitable diagnostic journey and assess corresponding phenotype and clinical characterization.
SN - 2077-0383
ER -