Biochemical Diseases Clinical Service, BC Children's Hospital, Vancouver, BC, Canada.
Gene. 2012 Apr 15;497(2):320-2. doi: 10.1016/j.gene.2012.01.056. Epub 2012 Jan 31.
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.
肥厚型心肌病（HCM）具有遗传异质性，主要由编码肌节蛋白的基因突变引起。然而，导致法布瑞病（一种 X 连锁溶酶体贮积症）的 GLA 突变也可能表现为孤立性 HCM。由于 HCM 基因检测面板在临床上的应用越来越广泛，未知意义的变异（VUS）时有出现，这给解释带来了挑战。我们呈现了一个说明性的案例：一名 10 岁女孩患有孤立性 HCM，在进行 HCM 多基因检测时，发现她携带了来自母亲的 GLA 上的 p.W24R 变异。试图通过直接对患者标本进行生化检测来评估该变异的意义，结果并不明确。随后的体外蛋白表达研究表明，该变异不太可能是致病性的。该病例突出了 VUS 通常会引发的诊断难题，特别是提出了一个问题，即是否应该将 GLA 测序纳入女性孤立性肥厚型心肌病患儿的一线诊断检测中。
