A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation

Several genetic conditions can lead to left ventricular hypertrophy (LVH). Among them, hypertrophic cardiomyopathy (HCM), caused by mutations in sarcomere genes, is the most common inherited cardiac disease. Instead, RASopathies, a rare class of disorders characterized by neuro-cardio-facial-cutaneous abnormalities and sometimes presenting with LVH, are caused by mutations in the RAS-MAPK pathway. We report on a 62-years-old male who presented isolated severe obstructive LVH but did not carry the sarcomere mutation previously identified in his affected relatives. By exome sequencing, we detected a novel mutation in HRAS gene (NM_005343.2:p.Arg68Trp), present also in the proband’s daughter, who showed mild LVH and severe intellectual disability. The cardiac phenotype was indistinguishable between family members carrying either mutation. In silico studies suggested that the mutated HRAS protein is constitutionally activated. Consistently, functional characterization in vitro confirmed elevated HRAS-GTP accumulation and downstream RAS-MAPK pathway activation that are known to drive cell proliferation in LVH. Our study emphasizes the role of RAS signaling in cardiac hypertrophy and highlights the complexity in differential diagnosis of RASopathies. In fact, the mild features of RASopathy and the recurrence of sarcomeric HCM in this family delayed the correct diagnosis until comprehensive genetic testing was performed.

多种遗传病症均可引发左心室肥厚（left ventricular hypertrophy, LVH）。其中，由肌节基因变异引发的肥厚型心肌病（hypertrophic cardiomyopathy, HCM）是最常见的遗传性心脏疾病。而RAS病（RASopathies）是一类罕见病症，以神经-心脏-面部-皮肤异常为特征，部分患者会出现LVH，其病因是RAS-MAPK通路发生变异。本研究报道1例62岁男性患者，其表现为孤立性严重梗阻性左心室肥厚，但未携带此前在其患病亲属中发现的肌节基因变异。通过外显子组测序，我们在HRAS基因中检测到1种新型变异（NM_005343.2:p.Arg68Trp），该变异同时存在于先证者的女儿体内，其女儿表现为轻度左心室肥厚与重度智力障碍。携带任意一种变异的家族成员，其心脏表型均无明显差异。计算机模拟研究显示，发生变异的HRAS蛋白呈结构性激活状态。与此一致的是，体外功能实验证实，HRAS-GTP的积聚量与下游RAS-MAPK通路的激活程度均有所升高，而这正是已知的驱动左心室肥厚相关细胞增殖的机制。本研究强调了RAS信号通路在心脏肥厚中的作用，并凸显了RAS病鉴别诊断的复杂性。事实上，该家族中RAS病的表现较为轻微，且肌节型肥厚型心肌病的复发情况，均导致正确诊断被推迟，直至完成全面的基因检测后方得以明确。