Alternative titles; symbols
ORPHA: 334; DO: 0050650;
Cytogenetic location: 10q22-q24 Genomic coordinates (GRCh38): 10:68,800,001-104,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22-q24 | Atrial fibrillation, familial, 1 | 608583 | Autosomal dominant | 2 |
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).
Genetic Heterogeneity of Familial Atrial Fibrillation
ATFB1 shows linkage to chromosome 10q22-q24. ATFB2 (608988) maps to chromosome 6q. ATFB3 (607554) is caused by mutation in the KCNQ1 gene (607542) on chromosome 11. ATFB4 (611493) is caused by mutation in the KCNE2 gene (603796) on chromosome 21. Variants in a region of chromosome 4q25 are associated with ATFB5 (611494). ATFB6 (612201) is caused by mutation in the NPPA gene (108780) on chromosome 1p36. ATFB7 (612240) is caused by mutation in the KCNA5 gene (176267) on chromosome 12p13. ATFB8 (613055) maps to chromosome 16q22. ATFB9 (613980) is caused by mutation in the KCNJ2 gene (600681) on chromosome 17q24.3. ATFB10 (614022) is caused by mutation in the SCN5A gene (600163) on chromosome 3p21. ATFB11 (614049) is caused by mutation in the GJA5 (121013) gene on chromosome 1q21.1. ATFB12 (614050) is caused by mutation in the ABCC9 gene (601439) on chromosome 12p12.1. ATFB13 (615377) is caused by mutation in the SCN1B gene (600235) on chromosome 19q13. ATFB14 (615378) is caused by mutation in the SCN2B gene (601327) on chromosome 11q23. ATFB15 (615770) is caused by mutation in the NUP155 gene (606694) on chromosome 5p13. ATFB16 (see 613120) is caused by mutation in the SCN3B gene (608214) on chromosome 11q24. ATFB17 (see 611819) is caused by mutation in the SCN4B gene (608256) on chromosome 11q23. ATFB18 (617280) is caused by mutation in the MYL4 gene (160770) on chromosome 17q21.
Olesen et al. (2014) analyzed 192 Danish Caucasian patients with onset of lone atrial fibrillation before the age of 40 years for the presence of rare variants in 14 AF-associated genes and found that 29 (7.6%) alleles harbored a very rare variant (minor allele frequency less than 1%), a significantly higher percentage than that found in 6,503 individuals in the NHLBI Exome Variant Server database (4.1%; p = 0.0012). Twenty-four of the 29 rare variants found in the lone AF patient cohort had previously been studied, with 23 (96%) showing abnormal ion channel function by patch-clamp analysis. Olesen et al. (2014) suggested that rare variants in AF susceptibility genes may play a role in the pathophysiology of AF.
Brugada et al. (1997) reported a Spanish family in which 10 members spanning 3 generations had atrial fibrillation segregating as an autosomal dominant trait. Nine family members had chronic atrial fibrillation and 1 had paroxysmal atrial fibrillation. Two additional members were known to have died from complications of atrial fibrillation, presumably embolic cerebrovascular accidents, at 36 and 68 years of age. Brugada et al. (1997) also reported 2 other Spanish families with a total of 9 affected members. The age at diagnosis of atrial fibrillation ranged from 2 to 46 years in the 3 families.
Tsai et al. (2008) reviewed the mechanisms underlying atrial fibrillation and the loci and genes associated with familial and nonfamilial atrial fibrillation. The data suggested that genes related to ionic channels, calcium-handling proteins, fibrosis, conduction, and inflammation play important roles in the pathogenesis of common atrial fibrillation.
In a Spanish family with 26 living members, 10 of whom had atrial fibrillation, Brugada et al. (1997) identified a disease locus at chromosome 10q22-q24 (lod score of 3.60 at markers D10S569 and D10S607). Two other families with 5 and 4 cases of atrial fibrillation, respectively, showed linkage to the same markers; lod scores of 6.02 and 5.35 for markers D10S569 and D10S607, respectively, were obtained when data on all 3 families were combined. The results were obtained by pooling the DNA of affected family members and comparing the results of the DNA analysis to those of an analysis of pooled DNA from unaffected family members at each of many marker loci. By this method, they identified 4 potential loci before performing conventional linkage analysis. Brugada et al. (1997) pointed out that the genes for the beta-adrenergic receptor (ADRB1; 109630) and alpha-adrenergic receptor (ADRA2; 104210) are located on 10q24-q26 as is also a gene for G protein-coupled receptor kinase (GPRK5; 600870), which interacts with adrenergic receptors. These are candidate genes for the site of the mutation in the linked families.
Associations Pending Confirmation
In a metaanalysis of genomewide association studies conducted using 1,335 individuals with lone atrial fibrillation and 12,844 unaffected individuals, Ellinor et al. (2010) identified an association on chromosome 1q21.3 to lone AF. The most significant SNP was rs13376333 (adjusted odds ratio, 1.56; p = 6.3 x 10(-12)), located in intron 1 of the KCNN3 gene (602983). The association was replicated in 2 independent lone AF cohorts (combined p = 1.83 x 10(-21); odds ratio, 1.52). Ellinor et al. (2010) noted that although KCNN3 is a plausible candidate gene for lone AF, the associated SNPs may lie within or serve as proxies for noncoding regulatory elements that might affect gene expression at considerable distances from their genomic locations. See also ATFB11 (614049) on chromosome 1q21.1.
Volders et al. (2007) studied a 4-generation Dutch family segregating autosomal dominant AF, with 10 likely affected family members, of which 6 had AF documented by electrocardiography (ECG). Mean age of onset was 51 years (range, 40 to 58 years); 4 affected individuals had persistent AF at the time of diagnosis and AF was permanent at the time of the study. Symptoms included chest discomfort, palpitations, and dizziness, and 2 patients presented with transient cerebral ischemic attacks prior to recognition of the cardiac arrhythmia. After exclusion of AF-associated genes and loci and other candidate genes, the authors performed genomewide microsatellite marker analysis and demonstrated 2-point lod scores greater than 1 (theta = 0) only across regions of chromosome 10. Fine mapping yielded a maximum 2-point lod score of 4.1982 at D10S568. Recombination in affected individuals narrowed the shared region of a 16.4-cM interval between markers D10S578 and D10S1652, at 10p11-q21. The 13 candidate genes within the interval were screened but no mutations in coding regions were found. Three younger members (16 years, 21 years, and 30 years of age) in the fourth generation of the family with a positive haplotype experienced chest discomfort and palpitations but did not show AF on ECG, and were designated as having an uncertain phenotype; however, the authors noted that they exhibited frequent supraventricular extrasystoles on 48-hour ECGs that were not observed in 12 unaffected family members.
Ellinor et al. (2005) performed a family study to evaluate the increased relative risk of 'lone' (i.e., isolated) atrial fibrillation. They found that family members had an increased relative risk of atrial fibrillation compared to the general population (risk ratio; 95% confidence intervals): sons (8.1; 2.0-32), daughters (9.5; 1.3-67), brothers (70; 47-102), sisters (34; 14-80), mothers (4.0; 2.5-6.5), and fathers (2.0; 1.2-3.6). The findings were interpreted as indicating a mendelian genetic contribution to the etiology of this common trait.
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]
Ellinor, P. T., Lunetta, K. L., Glazer, N. L., Pfeufer, A., Alonso, A., Chung, M. K., Sinner, M. F., de Bakker, P. I. W., Mueller, M., Lubitz, S. A., Fox, E., Darbar, D., and 50 others. Common variants in KCNN3 are associated with lone atrial fibrillation. Nature Genet. 42: 240-244, 2010. [PubMed: 20173747] [Full Text: https://doi.org/10.1038/ng.537]
Ellinor, P. T., Yoerger, D. M., Ruskin, J. N., MacRae, C. A. Familial aggregation in lone atrial fibrillation. Hum. Genet. 118: 179-184, 2005. [PubMed: 16133178] [Full Text: https://doi.org/10.1007/s00439-005-0034-8]
Olesen, M. S., Andreasen, L., Jabbari, J., Refsgaard, L., Haunso, S., Olesen, S.-P., Nielsen, J. B., Schmitt, N., Svendsen, J. H. Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation. Heart Rhythm 11: 246-251, 2014. [PubMed: 24144883] [Full Text: https://doi.org/10.1016/j.hrthm.2013.10.034]
Tsai, C.-T., Lai, L.-P., Hwang, J.-J., Lin, J.-L., Chiang, F.-T. Molecular genetics of atrial fibrillation. J. Am. Coll. Cardiol. 52: 241-250, 2008. [PubMed: 18634977] [Full Text: https://doi.org/10.1016/j.jacc.2008.02.072]
Volders, P. G. A., Zhu, Q., Timmermans, C., Eurlings, P. M. H., Su, X., Arens, Y. H., Li, L., Jongbloed, R. J., Xia, M., Rodriguez, L.-M., Chen, Y. H. Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21. Heart Rhythm 4: 469-475, 2007. [PubMed: 17399636] [Full Text: https://doi.org/10.1016/j.hrthm.2006.12.023]