A Novel Mutation In The EMD Gene Caused Familial Dilated Cardiomyopathy

Dilated cardiomyopathy （DCM） is the most common type of cardiomyopathy characterized by dilatation and impaired systolic function. Genetic factors are the major cause of familial DCM （FDCM）. Currently over40individual genes have been implicated in inherited DCM. The EMD gene, consisting of6exons and encoding emerin protein （254amino acids）, is the disease-causing gene of X-linked Emery-Dreifuss muscular dystrophy （EDMD）, which presented early-onset contractures of tendons, progressive muscular weakness and cardiomyopathy. To date, about100mutations have been reported in EMD gene and the majority of them had been identified in typical EDMD patients who suffered apparent both heart and skeletal muscle dysfunction. Atypical clinical features such as isolated cardiac diseases without apparent skeletal symptoms caused by EMD mutations only had been reported in rare cases. Thus, the EMD gene was not listed in the routine screening of non-syndromic DCM.Objective:To identify the disease-causing gene and mutation of a X-linked FDCM pedigree spanning five generations and consisting of73family members.Methods:We studied the X-linked FDCM pedigree using a combined strategy of whole exome sequencing （WES） and linkage analysis.Results:In the linkage analysis located region, a missense variation in the GPR50gene （c.113C>T, rs189225995） was found co-segregated with the disease phenotype. But no functional alteration was detected in the variant GPR50protein. When analyzing the failure sequences in the WES data, a14-bp deletion mutation in EMD exon1（c.26₃9delATACCGAGCTGACC） with no record in human gene mutation database （HGMD） was identified in this family. This mutation will cause a frameshift and a premature stop codon at the27th amino acid, resulting in almost a complete loss of emerin protein. However, different from the typical clinical features of EDMD caused by most reported EMD mutations, the patients in our study presented very mild skeletal atrophy that had not been diagnosed until the mutation was found.Conclusion:We found a novel EMD mutation in a large Chinese family with DCM. This mutation will result in almost a complete loss of emerin protein. However, the patients in our study presented severe cardiac muscle dysfunction but very mild skeletal muscle disorder. Our findings suggested that EMD mutation carriers could be diagnosed as DCM because of extremely mild skeletal myopathy and the screening of EMD gene in patients with isolated DCM of unknown etiology should be strongly recommended.