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Peer-reviewedCC BY 4.0PLOS One

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

  • Laura van Dussen1
  • Emilie V. Albers2
  • Saskia N. van der Crabben3
  • Ronald H. Lekanne Deprez
  • Astrid S. Plomp
  • Mirjam Langeveld
  1. 1Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  3. 3Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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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.

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Cite

BibTeXRIS
BibTeX
@article{dussen2026changing,
  title = {{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}},
  author = {Laura van Dussen and Emilie V. Albers and Saskia N. van der Crabben and Ronald H. Lekanne Deprez and Astrid S. Plomp and Mirjam Langeveld},
  journal = {PLOS One},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pone.0358572},
  url = {https://doi.org/10.1371/journal.pone.0358572},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 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
AU  - Laura van Dussen
AU  - Emilie V. Albers
AU  - Saskia N. van der Crabben
AU  - Ronald H. Lekanne Deprez
AU  - Astrid S. Plomp
AU  - Mirjam Langeveld
PY  - 2026
DA  - 2026/09/16
JO  - PLOS One
DO  - 10.1371/journal.pone.0358572
UR  - https://doi.org/10.1371/journal.pone.0358572
AB  - 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.
SN  - 1932-6203
ER  -