Bulmer Linda, Ljungman Charlotta, Hallin Johan, Dahlberg Pia, Polte Christian L, Hedberg-Oldfors Carola, Oldfors Anders, Gummesson Anders
Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Eur J Hum Genet. 2025 Mar 10. doi: 10.1038/s41431-025-01827-8.
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.
EMD基因的致病性变异会导致X连锁1型埃默里-德赖富斯肌营养不良症（EDMD1），其典型表现为关节挛缩和骨骼肌萎缩，随后出现房性心律失常、心脏传导缺陷和心房扩张。尽管有人提出该基因与孤立性扩张型心肌病（DCM）有关，但目前证据不足以证实这种基因与疾病的关联。我们在一个有DCM病史且男性疑似心源性猝死（SCD）的大家族中，研究了EMD基因中一个错义变异c.23C>G（p.Ser8Trp）的因果关系。6名年龄在36至50岁的半合子男性被诊断为DCM，详细的表型分析确定终末期心力衰竭、心脏传导缺陷和室性心律失常为突出特征。心脏磁共振成像显示钆延迟强化，呈现混合性缺血和非缺血模式。所有6名男性均无肌营养不良，其中5人接受了包括血清肌酸激酶测量在内的神经肌肉检查。免疫组化分析显示，心脏和骨骼肌样本中的emerin水平大幅降低。EMD变异c.23C>G与DCM共分离，估计LOD评分为3.9，全似然贝叶斯因子>2500:1，支持因果关系。在17名年龄在20至87岁的杂合子女性中，有1人在72岁时患上DCM。我们得出结论，EMD c.23C>G错义变异在无肌营养不良的情况下与DCM相关，从而为孤立性DCM作为一种与EDMD1不同的独特心脏EMD表型提供了新证据。与LMNA - DCM的表型相似性，伴有心脏传导缺陷和室性心律失常高风险，可能需要早期干预以预防SCD。
