Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.

中文翻译：

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外显子组测序确定CASK和MYBPC3中的突变是复杂的扩张型心肌病表型的原因。

现在，用于临床应用的全外显子组测序已成为医学遗传学实践不可或缺的一部分。尽管大多数研究都是为了在罕见的和临床上无法识别的疾病中进行诊断，但是由于成本和商业可用性的不断降低，全基因组测序已逐渐成为研究临床上公认的疾病患者的最初工具，而超过一个当一个以上基因的变异可能是造成这种疾病的原因时，基因负责表型或复杂表型。在这里，我们报道了一名患者，其表现为复杂的表型，包括严重的，成年发作的扩张型心肌病，听力下降和发育迟缓，其中外显子组测序显示了两个遗传变异，这些变异是从健康母亲那里继承的：CASK基因中的一种新的错义变体，其中的突变会引起一系列的神经认知表现，而MYBPC3中的第二种变体与遗传性心肌病有关。我们得出的结论是，尽管在分析近亲家庭的不确定表型时罕见病的同时发生可能性更高，但在非近亲家庭的复杂表型的遗传评估中也应考虑到这一点。