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

作者：Al Thihli Khalid^*; Ebrahim Hatim; Hughes Derralynn A; Patel Millan; Tipple Marion; Salvarinova Ramona; Gardiner Jane; Vallance Hilary; Waters Paula J

来源：Gene, 2012, 497(2): 320-322.

DOI：10.1016/j.gene.2012.01.056

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

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 CIA. 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 GM sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.

• 出版日期2012-4-15