Introduction: Atrial fibrillation (AF) is a heritable disorder with male predilection, suggesting a sex chromosome defect in certain patients. Loss-of-function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait. This study sought to identify the genetic basis for male-restricted, nonsyndromic sinus node dysfunction and AF in a multigenerational family.
Methods and results: Genealogical and medical records, and DNA samples, were obtained. Progressive SND and AF occurred in four males related through maternal lineages, consistent with X-linked inheritance. Skeletal myopathy was absent, even at advanced ages. Targeted X chromosome genotyping mapped the disease locus to Xq28, implicating EMD as a positional candidate gene. DNA sequencing revealed hemizygosity for an in-frame 3-bp deletion in EMD (Lys37del) in affected males, disrupting a residue within the LEM binding domain critical for nuclear assembly but leaving the remainder of the protein intact. Buccal epithelial cell staining with emerin antibody demonstrated near-total functional loss of emerin. Female relatives underwent prospective electrocardiographic and genetic testing. Those heterozygous for Lys37del had approximately 50-70% emerin-positive nuclei and variable degrees of paroxysmal supraventricular arrhythmia.
Conclusions: Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.