PLoS One. 2026 Sep 16;21(9):e0358572. doi: 10.1371/journal.pone.0358572. eCollection 2026.
ABSTRACT
Fabry disease (FD) is the most common lysosomal storage disorder in which a severe, classical phenotype as well as a milder, non-classical phenotype can be distinguished. In this study we investigated the impact of the introduction of broader DNA sequencing techniques and subsequently the addition of the GLA-gene to NGS or WES based panels on the type of FD patient that is diagnosed by analyzing changes in the composition of the Dutch Fabry cohort over time. The current study confirms that Fabry disease is a genetically heterogeneous disorder with 64 different GLA variants established in a cohort of 319 patients. The introduction of broader DNA sequencing techniques, applied to a broader range of individuals with less specific symptoms, results in the identification of a higher proportion of individuals with less deleterious GLA variants and consequently a milder clinical phenotype. For the majority of individuals identified using the broader sequencing techniques cardiomyopathy is the presenting and only symptom of the disorder, in contrast to the multisystem classical Fabry disease phenotype. This phenotypic shift should be taken into account when comparing current to historical clinical and treatment effect data and requires tailored genetic counseling and clinical follow-up to prevent both over- and undertreatment.
PMID:42748083 | DOI:10.1371/journal.pone.0358572