ReviewGenetics of vasovagal syncope
Introduction
Vasovagal syncope (VVS) is the most frequent type of syncope and affects about 25% of the population at least once during life (Chen et al., 2006, Ganzeboom et al., 2006, Thijs et al., 2006). VVS may lead to severe injuries and recurrent VVS reduces the quality of life (Rose et al., 2000, Santhouse et al., 2007). Therapeutic options for VVS are limited (Moya et al., 2009) and the development of new therapeutic strategies is hampered by the elusive pathophysiology (Mosqueda-Garcia et al., 2000).
The involvement of genetic factors in VVS has long been debated (Bizios and Sheldon, 2009, Olde Nordkamp et al., 2009) but current evidence strongly suggests a major genetic component. In this review we will discuss the clinical and molecular genetic findings in VVS.
Section snippets
Family aggregation studies
Family aggregation studies examine if affected individuals with a certain disease are more likely to have affected family members with this disease than healthy controls. A significant difference in the frequency of affected relatives is considered evidence for a genetic contribution to the disease of interest. Several family aggregation studies have been performed for VVS.
Camfield and Camfield reviewed the family history of 30 children with VVS and their unaffected best friends (Camfield and
Twin studies
Twin studies are a powerful method to detect the presence and contribution of genetic factors to a disease by comparing the concordances of monozygous and dizygous twins. Monozygous twins have virtually the same genomic DNA sequence. In contrast, dizygous twins share only 50% of their genomic DNA sequence like ordinary siblings. A twin pair is called concordant if both twins have developed the disease or feature of interest. As twins usually share the same environment, significant differences
Candidate gene association studies
The aim of candidate gene association studies is the identification of susceptibility genes for a disease of interest. Variants in susceptibility genes increase the likelihood for the development of a certain disease but are on its own not sufficient to cause the disease. Variants in multiple susceptibility genes and possibly additional environmental factors need to be present for the disease to develop (complex inheritance).
Candidate gene association studies are based on previous assumptions
Studies in large families
Another way to study the genetic influences on a particular disease is to study multiplex families with several affected family members. Of particular interest are families where the segregation of the disease is consistent with monogenic inheritance.
Autosomal dominant inheritance is a form of monogenic inheritance where a mutation in only one copy of a gene of major effect is responsible for the development of the particular phenotype. Children have a 50% chance of inheriting the abnormal gene
Genetic architecture of VVS
The current evidence clearly indicates that genetic factors play a major role in VVS. Genetic factors are particularly important when syncope occurs frequently or is associated with typical vasovagal triggers such as exposure to blood, injury, medical procedures, prolonged standing, pain or frightening thoughts. Genetic factors are less relevant when syncope occurs in the setting of strong environmental triggers such as dehydration or intercurrent illness.
There is a complex inheritance pattern
Conclusion
Current evidence demonstrates that genetic factors are relevant in VVS. It usually follows complex inheritance where multiple genes and probably environmental factors play a role. Less frequently VVS can be inherited in an autosomal dominant manner. Discovery of the underlying genetic determinants will help to improve our understanding of the pathophysiology and may lead to better treatment of subjects with frequent and disabling VVS in the future.
Acknowledgments
KMK was supported by a research fellowship from the Deutsche Forschungsgemeinschaft [KL 2254/1-1] and a scholarship from The University of Melbourne. SFB was supported by an NHMRC Australia Fellowship and an NHMRC Program Grant (ID: 628952).
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