X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Atrial fibrillation (AF) and sinus node dysfunction (SND) are heritable cardiac conditions with a male predilection.
• X-linked Emery-Dreifuss muscular dystrophy (EDMD) is caused by loss-of-function mutations in the EMD gene, affecting emerin, a nuclear membrane protein.
• This study investigated the genetic cause of male-restricted, nonsyndromic SND and AF in a multigenerational family.

Observation:

• Progressive SND and AF were observed in four males from the family, consistent with X-linked inheritance.
• Skeletal myopathy was notably absent in affected individuals.
• Genetic analysis identified a specific 3-bp deletion (Lys37del) in the EMD gene in affected males, leading to a near-total loss of emerin function in epithelial cells.

Findings:

• The EMD gene mutation (Lys37del) underlies X-linked familial AF and SND.
• This mutation causes emerin deficiency in epithelial cells, similar to EDMD, but results in electrical atriomyopathy without skeletal muscle involvement.
• Heterozygous female carriers exhibited partial emerin deficiency and variable supraventricular arrhythmias.

Implications:

• Mutation of EMD is a cause of X-linked familial AF.
• Targeted genetic testing of EMD is recommended for patients with SND-associated AF and a family history suggestive of X-linked inheritance.
• This research expands the known clinical spectrum of EMD mutations beyond EDMD.