Abstracts

Rationale: Vasovagal syncope (VVS) is the most frequent type of syncope and a common differential diagnosis of epilepsy. Using a twin-family design, we recently confirmed that VVS has a genetic etiology and showed that complex inheritance is usual (Klein et al. Neurology 2012 in press). Families consistent with autosomal dominant inheritance are also described in the literature. We previously reported a family with suggestive linkage to chromosome 15 (Klein et al. Epilepsia 2009;50(S11):149). Here, we describe an updated analysis of this family as well as five other families with autosomal dominant VVS, characterize the phenotype, refine the causative locus through linkage analyses and establish genetic heterogeneity. Methods: We recruited patients with VVS and a family history of syncope. A standardized questionnaire addressing features differentiating syncope from epilepsy was administered to all available family members. Medical records were obtained and additional diagnostic tests performed in selected individuals. Linkage analysis was performed in the largest family using SNP genotyping microarrays and in four other families with microsatellite markers for chromosome 15q26. Candidate genes within the linkage interval were analyzed by sequence analysis. Results: The largest family A contained 30 affected individuals over three generations with a median onset of 8-9 years. Five other families comprised between four and 14 affected individuals. The affected family members reported typical triggers of VVS such as sight of blood, injury, medical procedures, prolonged standing, pain and frightening thoughts. There was considerable variation of the triggers within the families. Linkage analysis revealed significant linkage to chromosome 15q26 in family A (LOD score 3.28) with two peaks, one at chromosome 15q26.1 spanning 6.28 cM or 1.7 Mb, and the other at chromosome 15q26.2 spanning 1.19 cM or 0.5 Mb. Linkage to chromosome 15q26 was excluded in two medium-sized families but not in two smaller families. No mutation was found in the candidate genes SLCO3A1, ST8SIA2 and NR2F2. Conclusions: The presented families demonstrate that familial VVS following autosomal dominant inheritance is not rare and has similar features to sporadic VVS. The refined genetic locus on chromosome 15q26 in the largest family increases the susceptibility to fainting but does not predispose to a particular vasovagal trigger. Genetic heterogeneity was established by linkage analyses in the other families. Identification of the causal mutations will help to further understanding of pathophysiology and guide further genetic research.