ORPHA: 334; DO: 0050650;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p22.2 | Atrial fibrillation, familial, 10 | 614022 | Autosomal dominant | 3 | SCN5A | 600163 |
A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-10 (ATFB10) is caused by heterozygous mutation in the SCN5A gene (600163) on chromosome 3p21.
Atrial fibrillation 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.
Laitinen-Forsblom et al. (2006) studied a large Finnish family in which 6 individuals had atrial arrhythmias and intraventricular conduction defects. Five affected family members presented with various atrial arrhythmias that developed in their second decade or later, including paroxysmal atrial flutter and fibrillation and ectopic atrial tachycardia. A deceased grandmother had atrial flutter, atrial fibrillation, and bradycardia, and a pacemaker had been implanted. Five of the affected individuals had a pacemaker implanted due to a conduction defect associated with symptomatic bradycardia. Intraventricular conduction delays, as shown by widening of the QRS complex and/or AV conduction defects, were demonstrated by ECG in all clinically affected individuals; typically, a slow AV junctional rhythm in the absence of P waves was seen. One clinically affected family member had an intraventricular conduction defect and atrial tachyarrhythmias, but no bradycardia. Echocardiography revealed an enlarged left ventricle with an increased end-diastolic left ventricular diameter in 1 affected individual, and the right ventricle was slightly enlarged in 3 affected individuals.
Ellinor et al. (2008) studied a 45-year-old white man with 'lone' atrial fibrillation and his affected father. The proband had onset of paroxysmal atrial fibrillation at 41 years of age. Echocardiography 3 years after the onset of AF revealed an ejection fraction of 55% with trace mitral and tricuspid valve regurgitation, and a left atrial diameter of 38 mm. The proband's 75-year-old father presented with syncope at 55 years of age and was found to be in atrial fibrillation; he was diagnosed with sick sinus syndrome and a pacemaker was placed. Echocardiogram 20 years after onset of AF revealed an ejection fraction of 58% with trace aortic insufficiency, mild mitral and tricuspid regurgitation, and a left atrial diameter of 43 mm.
In a large Finnish family with atrial fibrillation and conduction defects, Laitinen-Forsblom et al. (2006) performed linkage analysis using microsatellite markers flanking the candidate gene SCN5A on chromosome 3p21 and obtained a lod score of 3.09 with marker D3S1298. In addition, all affected individuals shared a common haplotype constructed from the marker data, suggesting that the SCN5A gene was involved in the predisposition to arrhythmia.
In a large Finnish family with atrial fibrillation (AF) and conduction defects, Laitinen-Forsblom et al. (2006) identified a heterozygous missense mutation (600163.0034) in the SCN5A gene that segregated with disease and was not found in more than 370 control chromosomes. Of 2 asymptomatic family members who carried the mutation, one had an abnormal electrocardiogram indicating intracardiac conduction defects, and the other was only 12 years old at the time of examination.
Ellinor et al. (2008) analyzed the SCN5A gene in 57 probands with a familial history of isolated or 'lone' AF and identified a missense mutation (600163.0041) in a 45-year-old white man and his affected father. The authors concluded that the SCN5A gene was not a major cause of familial AF.
Darbar et al. (2008) analyzed the SCN5A gene in 375 probands with AF, 118 of whom had lone AF, which was defined as AF occurring in individuals less than 65 years of age who did not have hypertension, overt structural heart disease, or thyroid dysfunction. A family history of AF was present in 99 (26%) of the 375 probands. Darbar et al. (2008) identified 8 heterozygous variants in 10 probands that were not found in 360 age-, sex-, and ethnicity-matched controls (see, e.g., 600163.0042-600163.0045). In addition, 11 previously reported rare nonsynonymous coding region variants were identified in 12 probands (see, e.g., 600163.0033), and 3 known common nonsynonymous SCN5A polymorphisms were also identified in the AF cohort (see, e.g., 600163.0024 and 600163.0031). Darbar et al. (2008) stated that in their study, nearly 6% of AF probands carried heterozygous mutations or rare variants in the SCN5A gene.
Brugada, R., Tapscott, T., Czernuszewicz, G. Z., Marian, A. J., Iglesias, A., Mont, L., Brugada, J., Girona, J., Domingo, A., Bachinski, L. L., Roberts, R. Identification of a genetic locus for familial atrial fibrillation. New Eng. J. Med. 336: 905-911, 1997. [PubMed: 9070470] [Full Text: https://doi.org/10.1056/NEJM199703273361302]
Darbar, D., Kannankeril, P. J., Donahue, B. S., Kucera, G., Stubblefield, T., Haines, J. L., George, A. L., Jr., Roden, D. M. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation 117: 1927-1935, 2008. [PubMed: 18378609] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.757955]
Ellinor, P. T., Nam, E. G., Shea, M. A., Milan, D. J., Ruskin, J. N., MacRae, C. A. Cardiac sodium channel mutation in atrial fibrillation. Heart Rhythm 5: 99-105, 2008. [PubMed: 18088563] [Full Text: https://doi.org/10.1016/j.hrthm.2007.09.015]
Laitinen-Forsblom, P. J., Makynen, P., Makynen, H., Yli-Mayry, S., Virtanen, V., Kontula, K., Aalto-Setala, K. SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias. J. Cardiovasc. Electrophysiol. 17: 480-485, 2006. [PubMed: 16684018] [Full Text: https://doi.org/10.1111/j.1540-8167.2006.00411.x]