Atrial Fibrillation, Familial, 6

A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-6 (ATFB6) is caused by heterozygous mutation in the NPPA gene (108780) on chromosome 1p36.

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

Hodgson-Zingman et al. (2008) reported a 3-generation Caucasian family of northern European ancestry in which 11 members were diagnosed with atrial fibrillation at a mean age of 40 years, in 3 cases during pregnancy. There was a transition from paroxysmal to chronic AF in 3 affected individuals and to arrest of atrial activation in 4 of them, suggesting progressive electrical remodeling. Tachycardia-induced cardiomyopathy was found in 5 subjects, which improved or resolved with effective pharmacologic rate control; subsequent echocardiography ruled out cardiac hypertrophy and contractile dysfunction, but showed dilation of the left atrial chamber in 7 patients and of the left ventricular chamber in 4 patients.

Abraham et al. (2010) studied a Caucasian kindred in which a mother and 2 children had relatively early-onset atrial fibrillation, with symptoms first appearing between 36 and 46 years of age. The proband developed palpitations, lightheadedness, and dizziness at age 36 years, and was diagnosed with paroxysmal lone AF at age 42, when an event recorder documented an episode of AF associated with rapid ventricular response. Family history revealed that his mother and older sister had been diagnosed with paroxysmal AF at the relatively young ages of 44 and 50 years. His mother subsequently developed hypertension and sick sinus syndrome, necessitating a permanent pacemaker at age 58. Two of the proband's children also reported occasional palpitations, but AF had not been documented.

Mapping

In a 3-generation family segregating autosomal dominant atrial fibrillation, Hodgson-Zingman et al. (2008) performed genomewide linkage analyses that ruled out known loci for atrial fibrillation. They obtained a peak 2-point lod score of 3.56 at marker D1S2667, and fine mapping identified a disease-associated haplotype spanning 24 Mb on chromosome 1p36-p35; a recombination event within this interval further narrowed the critical region to 11 Mb.

Molecular Genetics

Hodgson-Zingman et al. (2008) sequenced the candidate gene NPPA in a 3-generation family with atrial fibrillation and identified heterozygosity for a 2-bp deletion (108780.0001) that segregated with the disease and was not found in 560 controls.

In a cohort of 231 patients with atrial fibrillation, Abraham et al. (2010) analyzed the KCNQ1 (607542) and NPPA genes and identified heterozygosity for a missense mutation in NPPA (S64R; 108780.0002) in the proband of a Caucasian kindred segregating early-onset lone AF. The missense mutation segregated with disease in the family and was not found in Caucasian, Han Chinese, Asian, or African American population controls. Abraham et al. (2010) noted that ANP levels were not significantly different between family members with AF who were mutations carriers and those who were unaffected and did not carry the mutation. The authors also identified a mutation in the KCNQ1 gene (607542.0041) in another AF family (ATFB3; 607554) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism.

In a cohort of 384 Chinese AF patients and 844 controls, Ren et al. (2010) analyzed the NPPA SNP rs5063 but found no significant association. However, separate analysis involving only the 160 patients who were known to have lone AF showed significant association (p = 0.015; p = 0.003 after adjusting for age, gender, hypertension, diabetes, and smoking). The minor 'A' allele of rs5063 was found to confer a risk of lone AF with an odds ratio of 1.63, which increased to 1.89 after adjustment. Analysis of genotyping data under an additive, dominant, or recessive model showed significant association with lone AF for both an additive (p = 0.005) and a dominant (p = 0.007) model. Screening of the NPPA gene by direct sequencing revealed 3 probands with mutations that were not found in 844 controls, including 2 mutations in the 3-prime untranslated region and a missense mutation (I138T); however, all 3 families declined further genetic analysis. Ren et al. (2010) concluded that in addition to being a disease-causing gene, NPPA is a susceptibility gene for lone AF.