Why the Brugada syndrome is not yet a disease: Syndromes, diseases, and genetic causality

A syndrome is a collection of symptoms and clinical signs that often occur in concert and suggest a common cause. Contrary to a disease, the cause–effect relations and pathophysiological mechanisms of syndromes are unknown or at least incompletely understood. The unveiling of pathophysiological mechanisms underlying a syndrome is one of the most rewarding accomplishments of biomedical research. Definitions of a syndrome are often disputed (see, for example, the definition of heart failure 1), and its identifying signs may change. In some syndromes an association exists with a genetic mutation that is present in only a minority of patients. This apparent discrepancy can indicate that 1) standard genetic screening methods fail to detect mutations; 2) other (genetic) factors are required; 3) the genetic mutation establishes a modulating factor that is not causative but occurs in a higher frequency in the syndrome population. We will expand on these issues below. Failure to detect a mutation can result from methodological limitations. Koopmann et al. described a duplication of a large part of the DNA sequence in the gene encoding the pore-forming channel subunit for the rapidly activating delayed rectifier K+ current 2. The mutation was present in a family with long QT syndrome (LQTS) 2. Aberrancies of this type are not detected by conventional mutation screening techniques. Other causes for detection failure are the size of the gene, which practically prohibits mutation screening (e.g. RyR2 in arrhythmogenic right ventricular cardiomyopathy/dysplasia) 3, or incomplete knowledge of intronic and/or promoter regions. Second, the inferential presence of other (genetic) factors …