Abstract 3395: A Novel Locus on Chromosome 5 for Familial Atrial Fibrillation Associated with Prolonged Signal-Averaged P-wave
Background: While inherited forms of atrial fibrillation (AF) exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. The identification of ‘endophenotypes’ i.e., subtle or novel phenotypes that cosegregate with AF, may thus accelerate this effort.
Methods and Results: We performed a genome-wide linkage analysis in a large 4-generation kindred of 27 individuals, 8 with AF documented by ECG. The analysis was performed using AF as the phenotype, and repeated using an abnormally prolonged P-wave on signal averaged ECG as the phenotype. Subjects were considered unaffected with AF if they were >60 years of age, had no personal history of AF, and had no offspring with a history of AF. Linkage analysis and fine mapping generated a maximum multipoint logarithm of odds (LOD) score of 3.0 at chromosome 5p15 between markers D5S406 and D5S635, a span of 5.75 cM. Importantly, eight heterozygous carriers had a prolonged signal-averaged P-wave (203 ± 21 msec) compared with 10 non-carriers (121 ± 13 msec, P<0.000001). Using prolonged signal-averaged P-wave (conventionally defined as >155 msec) as an endopheno-type, a maximum multipoint LOD score of 2.8 was obtained in the same region of chromosome 5, spanning 6.4 cM.
Conclusions: In a large AF kindred, we have shown that affected individuals with AF can be identified by a prolonged signal-averaged P-wave, whereas non-carriers have normal P-wave duration. This strongly suggests that in this kindred, AF may be related to an atrial conduction disorder. Identification of the causal gene, mapped to chromosome 5p15, will be aided by ascertainment of additional family members using signal-averaged P-wave duration as an endophenotype.