Novel GLA Variants: 10 Experts’ Tips for the Clinical Assessment of Fabry Disease

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.