The introduction of broader DNA sequencing techniques results in the identification of a higher proportion of individuals with less deleterious GLA variants and consequently a milder clinical phenotype, requiring tailored genetic counseling and clinical follow-up to prevent both over- and undertreatment.
The Dutch Fabry cohort contains 319 patients with 64 different GLA variants, confirming that Fabry disease is a genetically heterogeneous disorder.
Introduction of broader NGS or WES based panels led to identification of a higher proportion of patients with less deleterious GLA variants and milder clinical phenotypes.
For the majority of individuals identified through broader sequencing techniques, cardiomyopathy is the presenting and only symptom of the disorder.
The composition of the Dutch Fabry cohort shifted over time as broader sequencing techniques were introduced, reflecting changes in how and in whom Fabry disease is diagnosed.
The phenotypic shift in newly diagnosed Fabry disease patients has important implications for the interpretation of historical clinical and treatment effect data.
Fabry disease is an inherited metabolic disorder caused by mutations in the GLA gene, which can cause a wide range of symptoms from severe multi-organ disease to milder, more limited forms. This Dutch study examined how the introduction of broader genetic testing methods — specifically next-generation sequencing (NGS) and whole exome sequencing (WES) panels that now include the GLA gene — has changed the types of patients being diagnosed with Fabry disease over time. By analyzing a cohort of 319 Dutch patients carrying 64 different GLA gene variants, the researchers found that modern sequencing approaches are identifying more people with milder, less damaging gene variants who predominantly have only heart muscle disease (cardiomyopathy), rather than the classic form of Fabry disease which affects multiple organ systems including the kidneys, nervous system, and skin. This research suggests that the profile of a 'typical' Fabry disease patient is changing not because the disease itself is changing, but because genetic testing is now being applied more broadly to people with less specific or less severe symptoms. The result is that a growing proportion of newly diagnosed individuals have a much milder form of the disease, often with heart involvement as their only symptom. This is a fundamentally different population from those historically diagnosed with Fabry disease, who tended to have the severe, classical multi-system form. The practical implications are significant: doctors and researchers can no longer straightforwardly compare today's patient outcomes or treatment responses to historical data, since the two groups may not be comparable. The findings also highlight the need for personalized genetic counseling and careful clinical monitoring for newly identified patients, to ensure they receive appropriate care — neither being undertreated if their condition is truly progressive, nor overtreated if their variant causes only minimal disease. This balance is especially important as Fabry disease has available but costly and burdensome enzyme replacement therapies.
van Dussen L, Albers E, van der Crabben S, Lekanne Deprez R, Plomp A, Langeveld M. (2026). The changing landscape of Fabry disease: Impact of the inclusion of the GLA-gene in broader NGS or WES based panels on the phenotypic spectrum.. PloS one. https://doi.org/10.1371/journal.pone.0358572