title: A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy.
abstract: Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, and largely caused by mutations in genes encoding sarcomere proteins. However, GLA mutations causing Fabry disease, an X-linked lysosomal storage disorder, may also present with isolated HCM. As HCM genetic testing panels are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a 10-year-old girl with isolated HCM who, on testing with a HCM multi-gene panel, was found to carry a maternally inherited p.W24R variant in GLA. Attempts to evaluate the significance of this variant, by direct biochemical testing of patient specimens, gave inconclusive results. Subsequent in vitro protein expression studies suggested that the variant is unlikely to be pathogenic. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether GLA sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.
authors.affiliation: Biochemical Diseases Clinical Service, BC Children's Hospital, Vancouver, BC, Canada. kalthihli@cw.bc.ca
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Thihli
authors.forename: Hatim
authors.initials: H
authors.lastname: Ebrahim
authors.forename: Derralynn A
authors.initials: DA
authors.lastname: Hughes
authors.forename: Millan
authors.initials: M
authors.lastname: Patel
authors.forename: Marion
authors.initials: M
authors.lastname: Tipple
authors.forename: Ramona
authors.initials: R
authors.lastname: Salvarinova
authors.forename: Jane
authors.initials: J
authors.lastname: Gardiner
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Waters
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D000795:Fabry Disease / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics; D035501:Uncertainty
chemical_list: D009124:Muscle Proteins