Published Online
on December 13, 2004

A more recent version of this article appeared on December 21, 2004

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Submitted on April 6, 2004
Revised on September 8, 2004
Accepted on September 24, 2004

Genome-Wide Linkage Scan Identifies a Novel Genetic Locus on Chromosome 5p13 for Neonatal Atrial Fibrillation Associated With Sudden Death and Variable Cardiomyopathy

Carlos Oberti MD, MS, Lejin Wang MD, Lin Li PhD, Jiamei Dong MD, Shaoqi Rao PhD, Wei Du BS, and Qing Wang PhD, MBA^*

From the Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute (C.O., L.W., L.L., J.D., S.R., W.D., Q.W.) and the Center for Cardiovascular Genetics, Department of Cardiovascular Medicine (C.O., L.W., L.L., J.D., S.R., W.D., Q.W.), The Cleveland Clinic Foundation; the Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (L.W., L.L., J.D., S.R., Q.W.), and the Department of Biological, Geological, and Environmental Sciences, Cleveland State University (W.D., Q.W.), Cleveland, Ohio; the Department of Cardiology, Ospedale Italiano Umberto I, Montevideo, Uruguay (C.O.); and Huazhong University of Science and Technology Human Genome Research Center, Wuhan, Hubei, P.R. China (Q.W.).

^* To whom correspondence should be addressed. E-mail: wangq2{at}ccf.org.

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.

Key words: arrhythmia • genetics • atrium • fibrillation • death, sudden

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