Abstract
<jats:p>Increasingly sophisticated genetic panels have disproportionately increased the identification rate of novel gene variants in Mendelian conditions. In Fabry disease (FD), this phenomenon is particularly relevant because the pathogenicity of individual gene variants has an impact on treatment proposal. In fact, FD is characterized by a phenotypical heterogeneity depending on patients' biological sex and the underlying GLA mutation. This represents the main reason why integrating genetic data with phenotypic expression is challenging, and defining the pathogenic role of novel variants remains complex. The early discrimination between pathogenic and non-pathogenic GLA variants is crucial to enable timely initiation of treatments such as Enzyme Replacement Therapy (ERT), which has been shown to significantly slow down the progression of the disease. 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 that have made 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 so to promptly start the most suitable diagnostic journey and assess corresponding phenotype and clinical characterization.</jats:p>