Clinical Heterogeneity in Sodium Channelopathies. What is the Meaning of Carrying a Genetic Mutation?

BACKGROUND: Mutations in the SCN5A gene have been linked to a variety of diseases causing sudden cardiac death, with important variability in expressivity and phenotypic overlap. With the availability of genetic testing family members may now be diagnosed as carriers based solely on the presence of the genetic defect. Clinical decision making in this situation is complex and generates important ethical and medicolegal issues. METHODS: We describe two families, 24-328 and 24-588, originally diagnosed with Brugada syndrome after the probands experienced cardiac arrest and we performed clinical and genetic analysis in their members. RESULTS: Both families had members with various electrocardiographic abnormalities including some with Brugada syndrome, long QT syndrome and conduction system disease. Both families had an important family history of sudden cardiac death. Direct sequencing of exons and exon-intron boundaries of the sodium channel gene SCN5A identified mutations in both families. CONCLUSIONS: These two families illustrate an increasingly common scenario when encountering families with ion channelopathies. Because a defibrillator is the only available therapeutic option at present in Brugada syndrome, physicians will be faced with extremely difficult therapeutic decisions that also have important legal, social and ethical implications, especially in children. These data indicate the need to develop guidelines on how to approach the results of genetic testing, especially in asymptomatic individuals.