Atrial Fibrillation, Familial, 18

A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-18 (ATFB18) is caused by mutation in the MYL4 gene (160770) on chromosome 17q21. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of atrial fibrillation, see ATFB1 (608583).

Clinical Features

Orr et al. (2016) studied a 3-generation family with atrial fibrillation (AF), conduction disease, and reduced left atrial function. The proband was a 32-year-old woman who presented at age 26 years with palpitations, at which time electrocardiography (ECG) showed atrial fibrillation with a slow ventricular rate response. During periods of sinus rhythm, extremely low amplitude P-waves and prolonged atrioventricular (AV) conduction (first-degree AV block) were observed. Intracardiac electrophysiologic studies demonstrated large areas of electrical silence within the left atrium, and some regions of the left and right atria showed rapid electrical signals consistent with ongoing atrial arrhythmia. Despite catheter ablation, the patient continued to experience paroxysmal AF. The proband's 53-year-old mother first presented with AF at age 32 years. She had a permanent pacemaker implanted at age 48 due to bradycardia in the setting of permanent AF. Echocardiography revealed an enlarged left atrial volume index and profoundly decreased left atrial function index, with normal biventricular size and function. The proband's 29-year-old sister presented at age 25 with palpitations and was found to have frequent episodes of AF; she also demonstrated very low amplitude P-waves and first-degree AV block on ECG. In addition, 48-hour ambulatory heart rate monitoring showed profound sinus bradycardia with sinus rates as low as 33 beats per minute. Echocardiography showed an enlarged left atrium and decreased left atrial function. Arrhythmia screening offered to other family members revealed a 22-year-old sister and a 50-year-old maternal uncle with permanent AF, and a 20-year-old cousin with low amplitude P-waves and first-degree AV block on ECG, but no AF.

Molecular Genetics

In a 3-generation family with atrial fibrillation, negative for mutation in 8 AF-associated genes, Orr et al. (2016) performed whole-exome sequencing and identified a heterozygous missense mutation in the MYL4 gene (E11K; 160770.0001) that segregated with disease in the family. The mutation was not found in 10 unrelated controls or in public variant databases. Sequencing of the MYL4 gene in 100 unrelated patients with isolated AF did not reveal any potentially pathogenic variants. Orr et al. (2016) noted that in large-scale whole-genome sequencing of the Icelandic population, Gudbjartsson et al. (2015) identified a founder frameshift mutation in MYL4 (c.234delC), which was present in 1.5% of the southern Icelandic population and associated with AF as a homozygous phenotype.