Genome-wide linkage scan identifies a novel genetic locus on chromosome 5p13 for neonatal atrial fibrillation associated with sudden death and variable cardiomyopathy

Abstract

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and patients with AF have a significantly increased risk for ischemic stroke. Approximately 15% of all strokes are caused by AF. The molecular basis and underlying mechanisms and pathophysiology of AF remain largely unknown.

Methods and results: We have identified a large AF family with an autosomal recessive inheritance pattern. The AF in the family manifests with early onset at the fetal stage and is associated with neonatal sudden death and, in some cases, ventricular tachyarrhythmias and waxing and waning cardiomyopathy. Genome-wide linkage analysis was performed for 36 family members and generated a 2-point logarithm of the odds (LOD) score of 3.05 for marker D5S455. The maximum multipoint LOD score of 4.10 was obtained for 4 markers: D5S426, D5S493, D5S455, and D5S1998. Heterozygous carriers have significant prolongation of P-wave duration on ECGs compared with noncarriers (107 versus 85 ms on average; P=0.000012), but no differences between these 2 groups were detected for the PR interval, QRS complex, ST-segment duration, T-wave duration, QTc, and R-R interval (P>0.05).

Conclusions: Our findings demonstrate that AF can be inherited as an autosomal recessive trait and define a novel genetic locus for AF on chromosome 5p13 (arAF1). A genetic link between AF and prolonged P-wave duration was identified. This study provides a framework for the ultimate cloning of the arAF1 gene, which will increase the understanding of the fundamental molecular mechanisms of atrial fibrillation.

Figure 1

Mapping of a novel genetic locus for autosomal recessive atrial fibrillation (arAF1). Pedigree structure of a family with autosomal recessive atrial fibrillation is shown. Genome-wide linkage analysis was performed with 398 polymorphic markers that span entire human genome by an average interval of 10 cM. Results of genotypic analysis are shown for markers D5S1506, D5S426, D5S493, D5S455, D5S1998, D5S1964, and D5S1490 below each individual. Affected individuals are shown as filled circles (females) and squares (males). Normal individuals are shown as empty symbols, and deceased individuals are indicated by slashes. Proband is indicated by an arrow. Obligate carriers by genotyping are denoted with black dots in symbols. Disease haplotype is denoted with a filled vertical bar, and normal haplotypes are indicated by open vertical bars. ECG analysis of normal family members and obligate heterozygous carriers did not reveal any clinical features of atrial fibrillation. Seven consanguineous marriages are indicated by =.

Figure 2

Multipoint LOD score analysis of atrial fibrillation (arAF1). Genotypes at D5S1506, D5S426, D5S493, D5S455, D5S1998, D5S1964, and D5S1490 were used to determine multipoint LOD scores at chromosome 5p13. D5S1506 is arbitrarily plotted at 0 cM at abscissa. Other microsatellite markers near arAF1 locus are indicated along abscissa from telomere to centromere. Multipoint LOD scores are plotted on ordinate.

Figure 3

Ideogram of chromosome 5 with Geimsa banding patterns and localization of arAF1 locus. Genetic map with chromosome 5p13 markers and location of putative arAF1 gene is shown on right.

Figure 4

ECG characterization of heterozygous carriers and noncarriers. A 2-tailed probability value was obtained by use of a Student’s t test with assumption of unequal variances and null hypothesis of no difference between mean values. Error bar represents SD. Only significant difference between carriers and noncarriers was identified for duration of P wave (P = 0.0000122). P wave indicates P-wave duration recorded from lead II (normal range for P-wave duration is from 80 ms to 100 ms); PR, length of PR interval; QRS, duration of QRS complex; ST, length of ST segment; T, T-wave duration; QT, length of QT interval; RR, length of RR interval; QTc, QT corrected for heart rate.