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


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.
Oberti
Carlos
C
Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Wang
Lejin
L
Li
Lin
L
Dong
Jiamei
J
Rao
Shaoqi
S
Du
Wei
W
Wang
Qing
Q
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D005260:Female; D005315:Fetal Diseases / Q000235:genetics; D005318:Fetal Heart / Q000503:physiopathology; D005808:Genes, Recessive; D015894:Genome, Human; D005838:Genotype; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017180:Tachycardia, Ventricular / Q000235:genetics; D014583:Uruguay / Q000453:epidemiology
D004247:DNA