Hypertrophic cardiomyopathy (HCM) is an inherited heart failure condition, mostly found to have genetic abnormalities, and is a leading cause of sudden death in young adults. Whole exome sequencing should be given consideration as a molecular diagnostic tool to identify disease-causing mutation/s. In this study, a HCM family with multiple affected members having history of sudden death were subjected to exome sequencing along with unaffected members. Quality passed variants obtained were filtered for rarity (MAF > 0.5%), evolutionary conservation, pathogenic prediction, and segregation in affected members after removing shared variants present in unaffected members. Only one non-synonymous mutation (p. Glu186Lys or E186K) in exon 6 of P2X7 gene segregated in HCM-affected individuals which was absent in unaffected family members and 100 clinically evaluated controls. The site of the mutation is highly conserved and led to complete loss of function which is in close vicinity to ATP-binding site-forming residues, affecting ATP binding, channel gating, or both. Mutations in candidate genes which were not segregated define clinical heterogeneity within affected members. P2X7 gene is highly expressed in the heart and shows direct interaction with major candidate genes for HCM. Our results reveal a significant putative HCM causative gene, P2X7, for the first time and show that germ-line mutations in P2X7 may cause a defective phenotype, suggesting purinergic receptor involvement in heart failure mediated through arrhythmias which need further investigations to be targeted for therapeutic interventions.

中文翻译：

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P2X7（与肥厚型心肌病相关的配体门控离子通道基因）功能丧失突变。

肥厚型心肌病（HCM）是一种遗传性心力衰竭疾病，多数发现具有遗传异常，并且是年轻人突然死亡的主要原因。应将整个外显子组测序作为鉴定致病突变的分子诊断工具。在这项研究中，具有多个猝死史的受影响成员的HCM家庭与未受影响的成员一起接受了外显子组测序。在去除未受影响成员中共有的变异后，对获得的质量合格的变体进行稀有性筛选（MAF> 0.5％），进化保守性，致病性预测和受影响成员中的隔离。P2X7外显子6中只有一个非同义突变（p。Glu186Lys或E186K）该基因在受HCM影响的个体中分离，而在未受影响的家庭成员和100个经过临床评估的对照中则没有。突变的位点是高度保守的，并导致完全丧失功能，该功能与ATP结合位点形成残基非常接​​近，从而影响ATP结合，通道门控或两者。未分离的候选基因突变定义了受影响成员内的临床异质性。P2X7基因在心脏中高度表达，并显示与HCM主要候选基因的直接相互作用。我们的结果首次揭示了一个重要的假定的HCM致病基因P2X7，并表明P2X7中的种系突变 可能会导致表型缺陷，提示嘌呤能受体参与由心律不齐介导的心力衰竭，需要进一步研究以针对性地采取治疗干预措施。