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Review
. 2022 Apr;101(4):390-402.
doi: 10.1111/cge.14102. Epub 2021 Dec 28.

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

Dominique P Germain  1   2 , Thierry Levade  3   4 , Eric Hachulla  5 , Bertrand Knebelmann  6 , Didier Lacombe  7   8 , Vanessa Leguy Seguin  9 , Karine Nguyen  10 , Esther Noël  11 , Jean-Pierre Rabès  2   12
Affiliations
Review

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

Dominique P Germain et al. Clin Genet. 2022 Apr.

Abstract

Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants in GLA. The phenotype varies depending on the GLA variant, alpha-galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non-pathogenic variants or variants of unknown significance (VUS). This, together with the non-specificity of some FD symptoms, challenges physicians attempting to interpret GLA variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease-specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several GLA VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re-analyzed through reviews of patients' charts. The same was done for pathogenic GLA variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease-specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach.

Keywords: ACMG criteria; Fabry disease; experts; genetic variants; pathogenicity interpretation; variants of unknown significance.

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Conflict of interest statement

D.P.G.: Consultant for Sanofi‐Genzyme, Idorsia, Takeda; speaker's honoraria from Takeda, Amicus, Sanofi‐Genzyme. T.L.: Hotel/travel grants from Sanofi‐Genzyme, Takeda, BioMarin, Enzyvant, Orphan. E.H.: Speaker's honoraria and/or travel grants from Sanofi‐ Genzyme, GSK, Actelion, Sobi; B.K.: Speaker's honoraria from Travere, Sanofi, Alnylam, Reata; hotel/travel grants from Sanofi, Travere, Reata; D.L.: Speaker's honoraria and hotel/travel expenses from Amicus, Sanofi‐Genzyme. V.L.S.: Speaker's honoraria from Sanofi‐Genzyme; hotel/travel grants from Amicus, Orphan, Takeda, Sanofi‐Genzyme; K.N.: Speaker's honoraria, travel grants from Sanofi Genzyme; grants from Amicus therapeutics; E.N.: Speaker's honoraria and/or travel grants from Amicus Therapeutics, Sanofi‐Genzyme. J.P.R.: Consultant for Sanofi‐Genzyme; hotel/travel expenses from Amicus Therapeutics; speaker's honoraria from Amgen.

Figures

FIGURE 1
FIGURE 1
Main clinical manifestations of Fabry disease (FD)
FIGURE 2
FIGURE 2
Most commonly reported types of GLA variants in the Human Gene Mutation Database (HGMD) and related Fabry disease (FD) phenotypes in hemizygous patients
FIGURE 3
FIGURE 3
Interpreting pathogenicity of genetic variants when facing uncertainty: lessons from Fabry disease (FD)
See this image and copyright information in PMC

References

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