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

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.

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

“…Many of these variants result in non-classic FD, with lesser organ involvement, later age of onset, and >5% of residual enzyme activity [5]. Moreover, many GLA variants of conflicting pathogenicity or unknown significance have been identified within screening programs for FD in newborns and high- risk populations [6]. In many individuals affected with these variants and presenting with atypical clinical features of FD, other factors may be contributing to disease pathogenesis besides the AGAL enzymatic deficiency and lysosomal storage.…”

“…Over the last two decades an increasing number of patients have been described with non-classic later-onset FD [5]. Many of these individuals have been identified by genetic screening of newborns or CKD populations [6], allowing the identification of new GLA variants and corresponding clinical manifestations [7, 8]. These individuals typically have missense GLA variants, varying levels of AGAL activity and a modest increase in plasma Gb3Cer.…”

Fabry’s Disease: The Utility of a Multidisciplinary Screening Approach

“…For each subject, all symptoms and signs associated with genetically defined FD were included in the above-mentioned institutional database, whereas those observed in subjects with VUS and benign or likely benign variants were excluded [ 27 ]. Regarding the multidisciplinary assessment at the time of diagnosis, several laboratory and instrumental exams were performed, in order to comprehensively define the occurrence, extent, and monitoring of different organ involvement ( Table 1 ).…”

Twenty years of the Fabry Outcome Survey (FOS): insights, achievements, and lessons learned from a global patient registry

“…Gb3 accumulation results in cell, tissue, and organ damage, leading to multisystem pathology typified by progressive renal and cardiovascular dysfunction; neuropathy; cerebrovascular events; ocular, dermatologic, gastrointestinal, and neuro-otologic manifestations; depression; and premature death [ 12 – 14 ]. Estimates of prevalence of FD range from approximately 1 in 117,000 to 1 in 37,000 live male births for classic FD and up to 1 in 1400 in some newborn screening projects when atypical FD variants are included [ 4 , 15 – 18 ]. As an X-linked disease, FD had originally been considered as a disease mainly affecting male patients; however, female patients who are heterozygous for GLA mutations can also be affected, although onset is later and phenotypes are more variable [ 6 , 13 ].…”