ORPHA: 334; DO: 0050650; MONDO: 0014340;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p13.2 | ?Atrial fibrillation 15 | 615770 | Autosomal recessive | 3 | NUP155 | 606694 |
A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-15 (ATFB15) is caused by homozygous mutation in the NUP155 gene (606694) on chromosome 5p13. One such family has been reported.
Atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. It is the most common sustained cardiac rhythm disturbance, and its prevalence increases as the population ages. An estimated 70,000 strokes each year are caused by atrial fibrillation (summary by Oberti et al., 2004).
For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.
Oberti et al. (2004) studied a large Uruguayan family segregating autosomal recessive atrial fibrillation that had early onset in the fetal stage and was associated with neonatal sudden death and, in some cases, ventricular tachyarrhythmias and waxing and waning cardiomyopathy. The proband was delivered by cesarean section at 36 weeks of pregnancy due to fetal tachycardia with a rate of 250 bpm and atrial fibrillation/flutter. Supraventricular tachyarrhythmias continued after delivery; echocardiogram at 2 days showed marked dilation of both atria and an ejection fraction of 52%. Electrophysiologic study at 1 month detected atrial fibrillation/flutter. After unsuccessful linear ablation of the left atrium, the patient underwent ablation of the atrioventricular node followed by placement of a permanent pacemaker because of the high frequency of sudden death in the family. At 2 months of age, only mild atrial dilation was observed, and the ejection fraction was borderline normal; at 4 months of age, the ejection fraction was 52%. The proband died suddenly at 15 months. He had 2 affected brothers; 1 was born with supraventricular tachycardia, and electrocardiography (ECG) at 24 days showed atrial flutter with a rate of 200 bpm. No structural heart abnormalities were detected by echocardiography at 24 days, but a later echocardiogram showed dilation of the left atrium and ventricle as well as decreased contractility with an ejection fraction of 43%; this brother died at 3 months of age. The proband's other brother was born with atrial tachycardia; echocardiography did not detect structural heart disease, and he died at 2 months of age. In another branch of the family, a female infant was born with atrial tachycardia, and cardioversion was performed at 20 days of age. An echocardiogram at age 1 month showed normal atrial and ventricular sizes. The infant died at 18 months of age. Her sister exhibited the typical features of AF on ECG, with absent or difficult-to-count P waves, fast atrial rate, and inconsistent R-R intervals; the QTc was 0.40 ms. Echocardiogram was normal at 15 months of age, and medical treatment appeared to maintain the patient in sinus rhythm with a heart rate of 125 bpm; however, she died suddenly at 19 months of age. All parents had a normal phenotype, and the sisters' mother and maternal grandmother had no structural cardiac anomalies on echocardiography.
Oberti et al. (2004) performed a genomewide scan in 36 members of a large Uruguayan family segregating autosomal recessive atrial fibrillation and obtained a peak 2-point lod score of 3.05 at marker D5S455 on chromosome 5p13 (theta = 0) using marker allele frequencies specific to the Uruguayan population. Fine mapping yielded a maximum multipoint lod score of 4.10 for a region spanned by 4 markers (D5S493, D5S426, D5S455, and D5S1998), and recombination events narrowed the disease locus to a 7.76-cM interval between D5S1506 and D5S1490. None of the 24 family members who were heterozygous carriers of the disease haplotype exhibited atrial fibrillation. Detailed analysis of ECG parameters in 19 heterozygous carriers and 5 noncarriers revealed a highly significant difference in P-wave duration between carriers and noncarriers (107 ms for carriers vs 85 ms for noncarriers; p = 0.0000122).
Zhang et al. (2008) restudied the Uruguayan family with autosomal recessive AF that was originally described by Oberti et al. (2004), into which a new affected male infant had been born. The maximum 2-point lod score increased to 4.04 in the expanded pedigree (theta = 0), and the maximum multipoint lod score increased to 4.40. Fine mapping restricted the 5p13 AF locus between the NPR3 (108962) and PTGER4 (601586) genes, and recombination events further defined the AF locus within a 5.75-Mb interval.
In a large Uruguayan family segregating autosomal recessive AF mapping to chromosome 5p13, originally studied by Oberti et al. (2004), Zhang et al. (2008) analyzed candidate genes and identified a homozygous missense mutation in NUP155 (R391H; 606694.0001) that segregated fully with disease in the family and was not found in 1,700 controls.
Exclusion Studies
In an Uruguayan family with neonatal-onset AF mapping to chromosome 5p13, Oberti et al. (2004) sequenced the candidate ion channel gene SLC1A3 (600111), but detected no mutations.
Zhang et al. (2008) generated a Nup155 knockout mouse line and observed that Nup155 +/- mice exhibited a sustained atrial fibrillation phenotype involving absence of discrete P waves and irregular R-R intervals on continuous telemetry electrocardiographic recordings. Electrophysiologic analysis of Nup155 +/- atrial myocytes showed a significantly shortened action potential duration compared to wildtype.
Oberti, C., Wang, L., Li, L., Dong, J., Rao, S., Du, W., Wang, Q. Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy. Circulation 110: 3753-3759, 2004. [PubMed: 15596564] [Full Text: https://doi.org/10.1161/01.CIR.0000150333.87176.C7]
Zhang, X., Chen, S., Yoo, S., Chakrabarti, S., Zhang, T., Ke, T., Oberti, C., Yong, S. L., Fang, F., Li, L., de la Fuente, R., Wang, L., Chen, Q., Wang, Q. K. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 135: 1017-1027, 2008. [PubMed: 19070573] [Full Text: https://doi.org/10.1016/j.cell.2008.10.022]