Background Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified GLA variants from the GLA-specific fabry-database.org database.
Methods A Fabry disease genotype–phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan–Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes.
Results Final consensus on classifications of ‘pathogenic’ was achieved for 32 of 33 GLA variants (26 ‘classic’ phenotype, 171 males; 6 ‘later-onset’ phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between ‘classic’ and ‘later-onset’ phenotypes.
Conclusion The iterative system implemented by a Fabry disease genotype–phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular GLA variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.
- expert opinion
- Fabry disease
- genotype-phenotype correlations
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Contributors DPG, JPO, DGB, HWY, RJH, JP, CW, WRW and DGW are members of the Fabry disease genotype–phenotype workgroup. DPG drafted the article. All authors have critically reviewed the manuscript for important intellectual content and are responsible for all content and editorial decisions. All authors approved the final version of the manuscript and received no honoraria related to the development of this publication.
Funding This research was funded by Sanofi Genzyme, the sponsor of the Fabry Registry. The authors received editorial/writing support in the preparation of this manuscript from Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme. DPG was supported by the Plan National Maladies Rares of the French Ministry of Health.
Disclaimer The funder had a role in Fabry Registry data collection and analysis.
Competing interests DPG is a consultant for Sanofi Genzyme and Takeda/Shire, was an investigator in clinical trials sponsored by Amicus Therapeutics and Sanofi Genzyme and has received speaker honoraria and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. JPO has received consulting honoraria and unrestricted research grants and funding for research projects from Sanofi Genzyme, has received speaker honoraria from Sanofi Genzyme and Takeda/Shire and has received conference and travel support from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. DGB has received speaker honoraria from Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire. HWY has received honoraria from Sanofi Genzyme. RJH has received consulting honoraria from Sanofi Genzyme, Amicus Therapeutics, Protalix Corporation and Takeda/Shire, was an investigator in clinical trials sponsored by Amicus Therapeutics, Sanofi Genzyme and Takeda/Shire and received research funding from Sanofi Genzyme, Protalix Corporation and Amicus Therapeutics; these activities have been monitored and found to be in compliance with the conflict of interest policies at Cincinnati Children’s Hospital Medical Center. RL is an employee of Sanofi Genzyme. JP has received honoraria and travel support from Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda/Shire. CW has received research support from Sanofi Genzyme and is a consultant for Actelion Pharmaceuticals, Protalix Corporation, Boehringer Ingelheim GmbH and Sanofi Genzyme. WRW consults for Sanofi Genzyme and was an investigator in clinical studies and trials sponsored by Amicus Therapeutics, Protalix Corporation, Sanofi Genzyme and Takeda/Shire and has received research funding from Sanofi Genzyme, Amicus Therapeutics and Takeda/Shire; these activities are monitored and are in compliance with the conflict of interest policies at Emory University School of Medicine. DGW received consulting honoraria from Amicus Therapeutics, Sanofi Genzyme, Actelion Pharmaceuticals, AVROBIO, Freeline Therapeutics and Protalix Biotherapeutics and has received research funding from Amicus Therapeutics and Sanofi Genzyme. DPG, JPO, DGB, HWY, RJH, JP and CW are Regional or International Fabry Registry Board members and have received Fabry Registry Board honoraria.
Patient consent for publication Not required.
Ethics approval The Fabry Registry protocol, informed consent form and any locally required authorisation documents are reviewed and approved by the local fully constituted Institutional Review Board or Independent Ethics Committee unless the site provides the Registry with documentation that approval is not required or has been waived.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Qualified researchers may request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Patient-level data will be anonymised and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.
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