Atrial Fibrillation, Familial, 7

A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-7 (ATFB7) is caused by heterozygous mutation in the KCNA5 gene (176267) on chromosome 12p13.

Description

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997).

For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.

Clinical Features

Olson et al. (2006) reported a 55-year-old female proband who had recurrent palpitations in childhood and was diagnosed with lone atrial fibrillation at age 35. Atrial fibrillation worsened over time, increasing to multiple daily occurrences. Rhythm control was refractory to pharmacotherapy and radiofrequency ablation, necessitating pacemaker implantation. Family history was positive for early-onset atrial fibrillation with diagnosis in 2 of the proband's brothers and an oldest niece. Palpitations consistent with paroxysmal disease were present in 2 younger sibs, all 3 of her children, and a youngest niece.

Christophersen et al. (2013) studied a Scandinavian woman who had onset of palpitations at age 16 years and documented persistent atrial fibrillation by age 18. Electrocardiogram (ECG) showed sinus rhythm with severely prolonged PR interval (360 ms), incomplete right bundle branch block, and prolonged QTc (490 ms). Her heart was structurally normal. Her son had episodes of palpitations and tachycardia beginning at 17 years of age, which increased in frequency and severity in his 20s. Event recordings and an exercise test revealed intermittent supraventricular extrasystoles and sinus tachycardia, but atrial fibrillation was not documented, and a 12-lead ECG was normal.

Molecular Genetics

Using a candidate gene approach, Olson et al. (2006) screened 154 unrelated individuals with isolated atrial fibrillation for mutations in the KCNA5 gene. In a female proband and 2 sibs with isolated atrial fibrillation, the authors identified heterozygosity for an E375X (176267.0001) mutation, which was not found in 540 control samples.

Yang et al. (2009) analyzed 12 known susceptibility genes in 120 unrelated Chinese families with atrial fibrillation and identified 3 mutations in KCNA5 in 4 probands (176267.0002-176267.0004), for an approximate total population prevalence of 3.3%. Two of the mutations were subsequently identified in 3 of 256 unrelated patients with sporadic atrial fibrillation.

Christophersen et al. (2013) analyzed the coding regions of the KCNA5 and KCNAB2 (601142) genes in 307 Scandinavian patients with onset of atrial fibrillation before 50 years of age and identified heterozygosity for 6 novel mutations in KCNA5 in 7 patients (see, e.g., 176267.0005 and 176267.0006), as well as several previously reported missense variants in 12 of the patients. None of the novel mutations were found in 216 controls or in 6,503 exomes from the Exome Variant Server (EVS) database. Only 1 KCNAB2 variant was detected in a patient, which was also found in 1 control and in 4 exomes in the EVS database. Functional analysis of the novel KCNA5 mutations demonstrated that 3 were gain-of-function changes, whereas the other 3 resulted in loss of function. Christophersen et al. (2013) noted that no other gene had been reported to have such a high frequency of rare variants associated with atrial fibrillation, suggesting that KCNA5 is among the most important genes involved in early-onset atrial fibrillation.