Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype-phenotype workgroup

J Med Genet. 2020 Aug;57(8):542-551. doi: 10.1136/jmedgenet-2019-106467. Epub 2020 Mar 11.

PMID: 32161151

Dominique P Germain, João Paulo Oliveira, Daniel G Bichet, Han-Wook Yoo, Robert J Hopkin, Roberta Lemay, Juan Politei, Christoph Wanner, William R Wilcox, David G Warnock

Summary: This study aimed to find a consensus phenotypic classification for previously unclassified GLA variants by using the GLA-specific fabry-database.org database. 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 developed classifications can aid in the clinical management of Fabry patients who have these variants.

Abstract

Background: The X-linked genetic disorder Fabry disease (α-galactosidase deficiency) is caused by a combination of pathogenic GLA variants. While there is considerable phenotypic heterogeneity, with two main types, classic and later-onset disease, clinical phenotypic adjudication is currently lacking for several variants. This study aimed to find a consensus phenotypic classification for previously unclassified GLA variants by using the GLA-specific fabry-database.org database.

Methods: A Fabry disease genotype–phenotype workgroup built a five-stage iterative system based on expert clinical evaluation, existing literature, and clinical evidence of pathogenicity using a 2-point scoring method based on clinical hallmarks of classic disease. Final validation was done using Kaplan–Meier (KM) analysis of severe clinical event-free survival. Web-based disease databases and in silico pathogenicity prediction programs were used to compare the results.

Results: For 32 of the 33 GLA variants, a final consensus on classifications of 'pathogenic' was reached (26 'classic' phenotype, 171 males; 6 'later-onset' phenotype, 57 males). One variant, however, remained of uncertain significance. When workgroup consensus classifications were applied to the established fabry-database.org database phenotypes, the KM curves remained identical, with the same separation between 'classic' and 'later-onset' phenotypes.

Conclusion: The Fabry disease genotype–phenotype workgroup used an iterative system to achieve phenotypic classifications for previously unclassified variants. Clinical pathogenicity associated with a specific GLA variant identified in affected males appears to have predictive value, and it also appears to correlate with risk for affected females. The newly developed classifications can aid in the clinical management of Fabry patients who have these variants.