EMD missense variant causes X-linked isolated dilated cardiomyopathy with myocardial emerin deficiency

Abstract Pathogenic variants in the EMD gene cause X-linked Emery–Dreifuss muscular dystrophy type 1 (EDMD1), typically presenting with joint contractures and skeletal muscle atrophy, followed by atrial arrhythmias, cardiac conduction defects, and atrial dilatation. Although an association with isolated dilated cardiomyopathy (DCM) has been suggested, evidence is currently insufficient to verify the gene-disease association. We investigated the causality of a missense variant, c.23C>G, p.Ser8Trp, in EMD in a large family with a history of DCM and suspected sudden cardiac death (SCD) in males. DCM was diagnosed in six hemizygous males aged 36–50 and detailed phenotyping identified end-stage heart failure, cardiac conduction defects, and ventricular arrhythmias as prominent features. Cardiac magnetic resonance imaging showed late gadolinium enhancement with mixed ischemic and non-ischemic patterns. Muscular dystrophy was absent in all six males, of whom five underwent neuromuscular examination including serum-creatine kinase measurement. Immunohistochemical analysis showed greatly reduced levels of emerin in both cardiac and skeletal muscle samples. The EMD variant c.23C>G co-segregated with DCM, with an estimated LOD score of 3.9 and full-likelihood Bayes factor of >2500:1 in favor of causality. Among the 17 heterozygous females, ages 20–87, one developed DCM at age 72. We concluded that the EMD c.23C>G missense variant is associated with DCM in the absence of muscular dystrophy, thereby providing new evidence of isolated DCM as a distinct cardiac EMD -phenotype, separate from EDMD1. The phenotypic similarities with LMNA -DCM, with a high risk of cardiac conduction defects and ventricular arrhythmias, might warrant early interventions to prevent SCD.