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Objective: To establish the occurrence of an autosomal dominant form of vasovagal syncope (VVS) by detailed phenotyping of multiplex families and identification of the causative locus., Methods: Patients with VVS and a family history of syncope were recruited. A standardized questionnaire was administered to all available family members and medical records were reviewed. Of 44 families recruited, 6 were suggestive of autosomal dominant inheritance. Genome-wide linkage was performed in family A using single nucleotide polymorphism genotyping microarrays. Targeted analysis of chromosome 15q26 with microsatellite markers was implemented in 4 families; 1 family was too small for analysis., Results: Family A contained 30 affected individuals over 3 generations with a median onset of 8 to 9 years. The other families comprised 4 to 14 affected individuals. Affected individuals reported typical triggers of VVS (sight of blood, injury, medical procedures, prolonged standing, pain, frightening thoughts). The triggers varied considerably within the families. Significant linkage to chromosome 15q26 (logarithm of odds score 3.28) was found in family A. Linkage to this region was excluded in 2 medium-sized families but not in 2 smaller families. Sequence analysis of the candidate genes SLCO3A1, ST8SIA2, and NR2F2 within the linkage interval did not reveal any mutations., Conclusions: Familial VVS, inherited in an autosomal dominant manner, may not be rare and has similar features to sporadic VVS. The chromosome 15q26 locus in family A increases the susceptibility to VVS but does not predispose to a particular vasovagal trigger. Linkage analysis in the remaining families established likely genetic heterogeneity.

Objective: Vasovagal syncope (VVS) is the most frequent type of syncope and a common differential diagnosis of epilepsy. The role of genetic factors in VVS is debated. We performed a twin-family study to clarify this question and to analyze the putative mode of inheritance., Methods: Fifty-one same-sex twin pairs where at least 1 had syncope were ascertained. The twins were interviewed via telephone using a standardized questionnaire. Available medical records were obtained. Information on the affected status of first- and second-degree relatives was acquired., Results: There was a trend toward higher casewise concordance in monozygous (MZ, 0.75) than dizygous (DZ, 0.50) twins for any syncope (p = 0.06). Significant and strong effects on concordance between MZ and DZ twins were found for fainting at least twice unrelated to external circumstances (0.71 vs 0.27, p = 0.018) and for syncope associated with typical vasovagal triggers (0.62 vs 0.00, p < 0.001). Twelve of 19 concordant MZ twin pairs reported sparse or no other affected family members whereas in the other 7 pairs multiple close relatives were affected., Conclusions: The twin analysis provides strong evidence for the relevance of genetic factors in VVS. Analysis of the families suggests that complex inheritance (multiple genes ± environmental factors) is usual, with rarer families possibly segregating a major autosomal dominant gene.