---
title: "Inclusion of the GLA-gene in NGS/WES panels alters the phenotypic spectrum of Fabry disease"
id: "plos-one-2-the-changing-landscape-of-fabry-disease-impact-of-the-inclusion-of-the-gla-gene"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-2-the-changing-landscape-of-fabry-disease-impact-of-the-inclusion-of-the-gla-gene"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572"
published_at: "2026-09-16T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Inclusion of the GLA-gene in NGS/WES panels alters the phenotypic spectrum of Fabry disease
## Provenance & Clinical Metadata
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- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572)
- **Published At:** 2026-09-16T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study analyzed the Dutch national Fabry disease cohort (Amsterdam UMC) to assess how broader DNA sequencing techniques and adding the **GLA-gene** to NGS/WES panels changed the types of patients diagnosed with **Fabry disease**. - The cohort comprised 319 individuals with pathogenic or likely pathogenic GLA variants, representing 64 unique variants; most variants were inherited (n = 275), with 8 de novo cases and 36 undetermined. - After introduction of broader sequencing (~2011), a higher proportion of individuals with **non-classical/attenuated** GLA variants were diagnosed compared to the era of single-gene testing (statistically significant differences reported; p < 0.001 and p = 0.004 for time-period comparison). - Broader testing identified more patients whose presenting and often sole manifestation was **cardiomyopathy**, rather than the multisystem classical phenotype characterized by childhood acroparesthesia, cornea verticillata and angiokeratoma. - For index patients, 68% of non-classical variants were identified via broad sequencing versus 22% of classical variants (p < 0.001). Overall, 24% of non-classical cases were diagnosed through broad techniques versus 7% of classical cases (p < 0.001). - The database contained six recurrent variants (I319T, P389A, R342Q, F18S, R220*, R112H) with variable family sizes; I319T (n = 43) was associated with a non-classical phenotype and genealogical analysis suggested distant relatedness to a common 18th/19th century ancestor. - Genealogical reconstruction and demographic modelling suggest many carriers, particularly for recurrent variants, may remain undiagnosed in the population. - The authors conclude that the phenotypic spectrum of diagnosed FD has shifted toward milder, cardiac-predominant presentations as a result of broader sequencing and GLA inclusion in panels, with implications for genetic counseling, follow-up, and interpretation of historical versus contemporary outcome data. - The study used retrospective registry data (export date December 2, 2025), included only variants classified pathogenic/likely pathogenic at time of testing, and excluded variants currently classified as benign. Details on some analyses (e.g., full raw data) were not provided due to privacy constraints.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosone%2Farticle%3Fid%3D10.1371%2Fjournal.pone.0358572) * * About * Browse * Publish * [](https://journals.plos.org/plosone/ "PLOS One") * Search [advanced search](https://journals.plos.org/plosone/search) * [Browse Topics](https://journals.plos.org/plosone/subjectAreaBrowse) Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click [here](https://github.com/PLOS/plos-thesaurus/blob/master/README.md "Link opens in new window"). [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572) [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572) * 0 [Save](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#savedHeader) * 0 [Citation](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#citedHeader) * 0 [View](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#viewedHeader) * 0 [Share](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572#discussedHeader) Open Access Peer-reviewed Research Article # 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 Dussen , Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing * E-mail: l.vandussen@amsterdamumc.nl Affiliation Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, University of Amsterdam, Amsterdam, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-6539-531X ](https://orcid.org/0000-0002-6539-531X "ORCID Registry") ⨯ * Emilie V. Albers, Roles Data curation, Formal analysis, Investigation Affiliation Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, University of Amsterdam, Amsterdam, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0005-1380-6673 ](https://orcid.org/0009-0005-1380-6673 "ORCID Registry") ⨯ * Saskia N. van der Crabben, Roles Writing – review & editing Affiliation Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-8619-1511 ](https://orcid.org/0000-0001-8619-1511 "ORCID Registry") ⨯ * Ronald H. Lekanne Deprez, Roles Writing – review & editing Affiliation Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-4687-0186 ](https://orcid.org/0000-0003-4687-0186 "ORCID Registry") ⨯ * Astrid S. Plomp, Roles Writing – review & editing Affiliation Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-4903-8232 ](https://orcid.org/0000-0002-4903-8232 "ORCID Registry") ⨯ * Mirjam Langeveld Roles Conceptualization, Investigation, Methodology, Resources, Supervision, Writing – original draft, Writing – review & editing Affiliation Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, University of Amsterdam, Amsterdam, The Netherlands [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-9934-6831 ](https://orcid.org/0000-0002-9934-6831 "ORCID Registry") ⨯ # 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 Dussen, * Emilie V. Albers, * Saskia N. van der Crabben, * Ronald H. Lekanne Deprez, * Astrid S. Plomp, * Mirjam Langeveld ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: September 16, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0358572) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0358572) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0358572) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0358572) * [Peer Review](https://journals.plos.org/plosone/article/peerReview?id=10.1371/journal.pone.0358572) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#abstract0) * [Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#sec001) * [Methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#sec002) * [Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#sec003) * [Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#sec004) * [Acknowledgments](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#ack) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0358572) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572) ## 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. ## Figures ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t002) ![Table 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t003) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g003) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g002) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t002) ![Table 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t003) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g003) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.t001) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0358572.g002) **Citation:** van Dussen L, Albers EV, van der Crabben SN, Lekanne Deprez RH, Plomp AS, 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 21(9): e0358572. https://doi.org/10.1371/journal.pone.0358572 **Editor:** Maria de Fátima Matos Almeida Henriques de Macedo, Universidade do Algarve, PORTUGAL **Received:** February 17, 2026; **Accepted:** September 2, 2026; **Published:** September 16, 2026 **Copyright:** © 2026 van Dussen et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All relevant data are within the paper and its Supporting Information files Both ethical and legal restriction prevent us from submitting our full raw data set. The dataset contains privacy sensitive information such as mutation, year of birth and gender which, given the rarity of Fabry disease, may lead to identification of individual patients despite being pseudonymized. We promote inclusive and collaborate research and anyone wishing to collaborate with us could contact the last author and, provided all conditions are met and a data sharing agreement is in place, raw data can be made available. **Funding:** The author(s) received no specific funding for this work. **Competing interests:** Mirjam Langeveld is involved in pre‐marketing studies with Sanofi and Chiesi. AMC Research BV manages all financial arrangements. No fees, travel reimbursements, subsidies or grants, related to the presented work or otherwise, have been obtained from pharmaceutical companies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. ## Introduction Fabry disease (FD, OMIM #301500) is the most common (X-linked) inherited lysosomal storage disorder and results from a deficiency in the enzyme alpha-galactosidase A, caused by deleterious variants in the _alpha-galactosidase (GLA)-gene_ (OMIM #300644). FD is a genetically heterogeneous disorder with over 1000 unique disease causing variants in the GLA-gene described to date [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref001)]. The estimated prevalence of FD varies, which is largely the result of differences in disease definition and phenotypic heterogeneity of the disorder. The classical FD phenotypes observed in male patients with very low, or absent enzyme activity, can be recognized by a triad of childhood onset symptoms: _neuropathic pain_ in the extremities _(acroparesthesia)_ which may be provoked by fever or physical exertion, _cornea verticillata_ in the eyes and _angiokeratoma_ in the skin. Complications of the disorder, which become clinically apparent from the fourth or fifth decade onwards, include renal failure, hypertrophic cardiomyopathy, cardiac rhythm disturbances, heart failure, myocardial infarction and stroke. Biochemically, substrate accumulation can be demonstrated by measuring high levels of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3, generally above 40 mmol/L) [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref002)]. In addition to this well-defined, well understood and relatively homogeneous form of the disease, there are individuals with significant (albeit variable) residual enzyme activity levels, lower Gb3 and lyso-Gb3 substrate levels and therefore a milder phenotype. This group includes male patients with less deleterious GLA variants, as well as female patients with deleterious GLA variants causing classical disease in males (milder in women because of the compensatory unaltered GLA copy on the second X chromosome). The disorder in this group of patients is often described as non-classical, atypical, or cardiac variant FD. In the female patients with severe GLA variants, cornea verticillata or acroparesthesia can be present, but angiokeratoma are seldom observed and the clinical course is dominated by cardiac manifestations. In both groups (females with deleterious variants and male patients with less deleterious variants) cardiac complications occur approximately a decade later compared to male patients with classical disease [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref003)], while renal and cerebral complications are far less prevalent. Clinical symptoms are hardly observed in female patients with less deleterious variants (leading to non-classical disease in males)or occur at an age at which complications may also be observed in a healthy cohort [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref003)]. Clinical suspicion of FD, should be confirmed genetically and this also serves to facilitate cascade genetic screening. Possibilities of broad DNA sequencing techniques in diagnostics have evolved over the past decade. While targeted testing of the GLA-gene by Sanger sequencing has been possible since the early 1990s, broader DNA sequencing techniques including Next Generation Sequencing (NGS) and Whole Exome Sequencing (WES) have been offered as diagnostic tools in Amsterdam UMC from approximately 2011 onwards. These techniques enable sequencing of a large number of genes, or even an (almost whole) exome or genome, in a single analysis. Analysis can be restricted to genes associated with specific signs or symptoms (panel analysis, e.g., for hypertrophic cardiomyopathy), can include all OMIM-associated disease genes (mendeliome analysis), or (mostly in research settings) identify candidate genes (open exome/genome analysis). Following the introduction of these techniques, the GLA-gene has been added to several NGS or WES based panels such as (hypertrophic) cardiomyopathy, renal disorders and polyneuropathies. The objective of this article is to describe the genetic and phenotypic heterogeneity in a large, single country FD cohort and to study the impact of the introduction of broader DNA sequencing techniques and subsequent inclusion of the GLA-gene in several NGS or WES based panels on the composition of this cohort. In addition, we aim to describe the origin of the identified variants (de novo or inherited). In addition we identified if different index patients (the first patient in a family in whom the genetic variant is identified) who were independently found to carry the same variant in the GLA-gene were (distantly) related to one another. Identifying a common ancestor can help make the distinction between inherited and de novo mutations, but also result in extra information on life expectancy in ancestors who were obligate carriers. ## Methods This is an observational longitudinal retrospective study, using data from all patients included in the Dutch national FD database. This database is maintained by the Inherited Metabolic Disease Expert Center of the Amsterdam University Medical Centers, the national referral center for patients with FD in the Netherlands. Patients with FD have been followed and have had their data recorded during outpatient clinic visits since 1999. All individuals included in this database gave written informed consent for use of their data for research purposes (Medical Ethics Committee Amsterdam UMC, CTB number 2014_192). An export of the database used in the analysis of this study was made on December 2nd 2025. Data in the database are pseudonymized and only authorized individuals have access to the key file in which information is linked to identifiable personal data. Genotype and phenotype data were collected, as well as the year in which DNA analysis was performed, and the indication for and type of genetic test (single gene versus broader DNA sequencing technique). In this analysis we started with inclusion of all patients in our national database with a GLA variant classified as pathogenic or likely pathogenic at the time the diagnostics were performed. For the vast majority of variants, this classification remained unchanged over time [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref004),[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref005)]. The following GLA variants, present in individuals part of our database, are currently classified as benign (not causing Fabry disease) P60L, A143T, D313Y, T385A, W277C and are thus excluded from the current analysis [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref006)]. The R112H variant _is_ included in this manuscript, but its pathogenicity has recently become subject of debate [[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref007)]. Fabry disease in male patients in our cohort is, irrespective of age, classified either as classical or non-classical based on the presence or absence of classical symptoms, untreated plasma lysoGb3 level and mutation and family history. Male patients are considered to have classical disease if they have one or more of the classical symptoms (cornea verticillata, angiokeratoma and/or acroparesthesia) and a plasma lysoGb3 level of >40 nmol/L [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358572#pone.0358572.ref002)]. If the untreated plasma lysoGb3 levels were unknown (n = 4), this was extrapolated from a male relative carrying the same variant or the first value under treatment. Fabry disease in male patients that does not meet these criteria is classified as non-classical Fabry disease. Female patients with Fabry disease are divided into two groups: those carrying deleterious variants (leading to classical disease in males) and those with the less deleterious variants (leading to non-classical disease in males). To investigate the impact of broader DNA analysis methods on phenotypic composition of the Dutch FD cohort, a Chi-squared test was conducted to compare the number of index patients with a classical/severe GLA variant versus those with the non-classical variants and the type of genetic testing performed (single gene vs broad sequencing). Similarly, the number of patients with a classical vs a non-classical variant identifi
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