扩张型心肌病（DCM）发病率高达1/250，发病机制并不完全清楚，导致治疗进展缓慢。遗传研究在发现疾病新致病机制中有先驱作用。DCM大部分遗传学基础尚不清楚，已知的致病基因只能解释40%的家族性DCM。我们对一排除已知致病基因的DCM家系，采用全外显子测序的方法，鉴定出NAG基因c.A5227G突变为唯一候选致病突变；该突变不存在于550例同族对照人群中。在22例排除已知致病基因的DCM患者中，1例同样携带NAG c.A5227G突变。NAG是选择性剪切-无义介导的mRNA降解（AS-NMD）调节过程的关键分子，后者在遗传疾病中有重要作用：多个AS-NMD调节分子如RBM20、Smg1、hnRNP U等功能改变均可导致心肌病。申请人拟完善遗传和功能证据，证明NAG是DCM新的致病基因，主要在调节心脏特异性分子的剪切和转录及细胞凋亡的方面阐述其致病机制；并首次阐述中国DCM患者致病基因图谱。

Dilated cardiomyopathy (DCM) represents the third most common cause of heart failure after coronary artery disease and hypertension. The pathogenic mechanisms of DCM remain unclear, the progress of treatment is quite slow, and the patients have poor prognosis. Genetic study could offer good opportunity in discovering new mechanism of diseases, which could be completely novel. The underlying genetic causes of roughly 60% of familial DCM (FDCM) cases remain unknown. Previously in a FDCM pedigree in which disease-causing variations in known cardiomyopathy genes have been ruled out, we identified a mutation in neuroblastoma amplified gene (NAG, c.A5227G) as the candidate disease-causing mutation of this family. This mutation is absent from 550 ancestry-matched normal Han Chinese individuals, and not found in the public databases including dbSNP, the 1000 Genome, ESP6500, and the ExAC databases. Also in 22 DCM patients not harboring disease-causing mutations in known cardiomyopathy genes, we sequenced the whole exomes and exome-intron boundaries of NAG gene, and found 1 patient present with this c.A5227G mutation. NAG is a critical regulator of the alternative splicing-nonsense mediated mRNA decay (AS-NMD) process, which is important and always involved in genetic diseases. Particularly, a number of AS-NMD factors, including RBM20, Smg1 and hnRNP U, have been reported to cause DCM phenotype in mice once they were mutated or knocked out. In our future work, we will confirm that NAG is a novel disease-causing gene of DCM from two aspects—the clinical genetic aspect and functional molecular aspect. We will focus on the splicing and transcriptional regulation of NAG on cardiomyocyte specific genes, and endoplasmic reticulum stress and cell apoptosis. We will also for the first time describe the atlas of clinical genetic of human dilated cardiomyopathy in Chinese population.