A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy

Khalid Al-Thihli, Hatim Ebrahim, Derralynn A. Hughes, Millan Patel, Marion Tipple, Ramona Salvarinova, Jane Gardiner, Hilary Vallance, Paula J. Waters

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)320-322
Number of pages3
JournalGene
Volume497
Issue number2
DOIs
Publication statusPublished - Apr 15 2012

Fingerprint

Hypertrophic Cardiomyopathy
Uncertainty
Genes
Fabry Disease
Sarcomeres
Mutation
Genetic Testing
Proteins

Keywords

  • α-Galactosidase A
  • Fabry disease
  • GLA
  • Hypertrophic cardiomyopathy
  • Variant of unknown significance

ASJC Scopus subject areas

  • Genetics

Cite this

A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy. / Al-Thihli, Khalid; Ebrahim, Hatim; Hughes, Derralynn A.; Patel, Millan; Tipple, Marion; Salvarinova, Ramona; Gardiner, Jane; Vallance, Hilary; Waters, Paula J.

In: Gene, Vol. 497, No. 2, 15.04.2012, p. 320-322.

Research output: Contribution to journalArticle

Al-Thihli, K, Ebrahim, H, Hughes, DA, Patel, M, Tipple, M, Salvarinova, R, Gardiner, J, Vallance, H & Waters, PJ 2012, 'A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy', Gene, vol. 497, no. 2, pp. 320-322. https://doi.org/10.1016/j.gene.2012.01.056
Al-Thihli, Khalid ; Ebrahim, Hatim ; Hughes, Derralynn A. ; Patel, Millan ; Tipple, Marion ; Salvarinova, Ramona ; Gardiner, Jane ; Vallance, Hilary ; Waters, Paula J. / A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy. In: Gene. 2012 ; Vol. 497, No. 2. pp. 320-322.
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AU - Tipple, Marion

AU - Salvarinova, Ramona

AU - Gardiner, Jane

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