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

Clin Genet. 2022 Apr;101(4):390-402. doi: 10.1111/cge.14102.

PMID: 34927718

Dominique P Germain, Thierry Levade, Eric Hachulla

Highlights: A panel of Fabry disease (FD) specialists convened to study how expertise may compare with the traditional approach.

Abstract

Background: Fabry disease (FD) is an X-linked genetic condition due to pathogenic variants in GLA. The patient's age, gender, GLA variation, residual alpha-galactosidase activity, and, for females, X chromosomal inactivation, all affect the phenotype. More than 1000 variants have been identified, many of which were found by screening procedures more likely to reveal non-pathogenic variants or variant of uncertain significance (VUS). The non-specificity of various FD symptoms and thus make it difficult for physicians to interpret GLA variations. The American College of Medical Genetics and Genomics' recommended in silico techniques are used in conjunction with allele frequencies, genomic databases, global and disease-specific clinical databases, and the traditional approach to evaluating pathogenicity.

Objective: A group of FD experts gathered in this instance to research how the traditional approach and expertise may compare.

Results and conclusion: Through examinations of patients' charts, certain GLA VUS that have received a lot of attention in the literature (p.Ser126Gly, p.Ala143Thr, and p.Asp313Tyr) were re-analyzed. With some exceptions, the same was done for pathogenic GLA variants. The findings indicate that the input of geneticists and physicians with extensive knowledge of disease prevalence, inheritance, biomarkers, allele frequencies, disease-specific databases, and literature significantly contributes to a more accurate interpretation of the pathogenicity of variants, providing a significant improvement over the conventional approach.

Keywords: ACMG criteria, Fabry disease, genetic variants, variants of unknown significance