A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance

Abstract

Screening for Fabry disease (FD) reveals a high prevalence of individuals with α-galactosidase A (GLA) genetic variants of unknown significance (GVUS). These individuals often do not express characteristic features of FD. A systematic review on FD screening studies was performed to interpret the significance of GLA gene variants and to calculate the prevalence of definite classical and uncertain cases. We searched PubMed and Embase for screening studies on FD. We collected data on screening methods, clinical, biochemical and genetic assessments. The pooled prevalence of identified subjects and those with a definite diagnosis of classical FD were calculated. As criteria for a definite diagnosis, we used the presence of a GLA variant, absent or near-absent leukocyte enzyme activity and characteristic features of FD. Fifty-one studies were selected, 45 in high-risk and 6 in newborn populations. The most often used screening method was an enzyme activity assay. Cut-off values comprised 10-55% of the mean reference value for men and up to 80% for women. Prevalence of GLA variants in newborns was 0.04%. In high-risk populations the overall prevalence of individuals with GLA variants was 0.62%, while the prevalence of a definite diagnosis of FD was 0.12%. The majority of identified individuals in high-risk and newborn populations harbour GVUS or neutral variants in the GLA gene. To determine the pathogenicity of a GVUS in an individual, improved diagnostic criteria are needed. We propose a diagnostic algorithm to approach the individual with an uncertain diagnosis.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events

“…[13][14][15][16] The eighth patient had a single variant (p.R118C) classified as GVUS. 8 Clinically, no patients exhibited the classic early-onset phenotype of Fabry. The late-onset, attenuated form of Fabry is therefore rare among the Canadian demographic ≤55 years presenting with cryptogenic IS or TIA: a prevalence value Heterozygous, exon 7 IVS6-22C>T, rs2071228 Homozygous, exon 7 IVS6-22C>T, rs2071228…”

“…Stroke July 2017 of 0.3% (95% CI, 0.0%-1.4%) being determined if pathogenicity of the p.R118C variant is eventually confirmed as per recently proposed diagnostic criteria 8 and 0.0% (95% CI, 0.0-1.0) if not. The very low prevalence we found is consistent with most previous studies based on various designs (Table 4).…”

“…Positive screens included any genetic variant labeled as pathogenic or GVUS. 8 Participants with positive screens were referred to specialized centers participating in the Canadian Fabry Disease Initiative …”

“…Some variants are known to be pathogenic, others are disease neutral or nonpathogenic, but many are genetic variants of unknown significance (GVUS). 8 Limited information is available on the prevalence of Fabry disease among patients with a cryptogenic stroke from North America. We therefore conducted the CFSSI (Canadian Fabry Stroke Screening Initiative), a large prospective multicenter cohort study of young Canadians with cryptogenic stroke or TIA undergoing predetermined etiologic investigation and follow-up.…”

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease

“…kidney or heart) showing storage characteristic of FD, according to strict histological criteria, can confirm the diagnosis in most cases (see Table A1) (Smid et al 2014;van der Tol et al 2015). However, a biopsy is invasive and cannot be performed in every patient.…”