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A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance
  1. L van der Tol1,
  2. B E Smid1,
  3. B J H M Poorthuis2,
  4. M Biegstraaten1,
  5. R H Lekanne Deprez3,
  6. G E Linthorst1,
  7. C E M Hollak1
  1. 1Department of Endocrinology and Metabolism, Amsterdam Lysosome Center ‘Sphinx’, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Laboratory of Genetic Metabolic Diseases, Amsterdam Lysosome Center ‘Sphinx’, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. 3Clinical Genetics, Amsterdam Lysosome Center ‘Sphinx’, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to
    Prof Dr C E M Hollak, Department of Endocrinology and Metabolism, F5-170, PO box 22660, Amsterdam 1105 AZ, The Netherlands; c.e.hollak{at}amc.uva.nl

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.

  • Fabry disease
  • Mass Screening
  • Neonatal screening
  • Genetic testing
  • Prevalence

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