Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported. Although rare, recessive mutations are thought to contribute considerably to DCM, especially in young children. Here we identified a novel recessive mutation in the striated muscle enriched protein kinase (SPEG, p. E1680K) gene in a family with nonsyndromic, early onset DCM. To ascertain the pathogenicity of this mutation, we generated SPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies in mutant iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization, recapitulating the hallmarks of DCM. By combining genetic analysis with human iPSCs, genome editing, and functional assays, we identified SPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicity in vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.

扩张型心肌病（DCM）是导致心力衰竭和猝死的常见原因。据估计，多达一半的DCM病例是遗传性的。已经报道了超过50个基因的突变，主要是常染色体显性遗传。尽管罕见，但隐性突变被认为对DCM有很大贡献，尤其是在幼儿中。在这里，我们确定了横纹肌一种新型的隐性突变丰富的蛋白激酶（SPEG，p。E1680K）基因在非综合征性家族，早发DCM。为了确定此突变的致病性，我们生成了SPEG使用CRISPR / Cas9介导的基因组编辑，E1680K纯合突变型人诱导多能干细胞衍生的心肌细胞（iPSC-CM）。在突变iPSC-CM中进行的功能研究表明，钙的动态平衡异常，收缩力降低和肌节解离，这重述了DCM的标志。通过遗传分析的人iPSC，基因组编辑，和功能分析相结合，我们确定SPEG E1680K与早发DCM相关的新突变，并提供了其致病的证据体外。我们的研究为建立具有常染色体隐性遗传的DCM中的基因型-表型关联提供了一个概念范式。