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.