Just over 50 years ago, in 1958, a 16-year-old male presented at one of our university hospitals (Groningen) because a routine sports examination had uncovered an abnormal electrocardiogram.
1 This presentation eventually revealed a family accompanied by premature (mostly nocturnal) sudden cardiac deaths throughout the last two centuries and currently involves over 1000 individuals in ten generations. Moreover, in 1999 it became clear that these deaths and the electrocardiographic abnormalities could be attributed to a single mutation in the cardiac sodium channel gene
SCN5a (1795insD).
2 Of particular interest, carriers of the mutation had electrocardiographic features of long-QT syndrome, Brugada syndrome and/or progressive cardiac conduction defects, referred to as an ‘overlap syndrome’, which was not yet described for cardiac channelopathies at that time. As expected in a founder mutation, most mutation carriers clustered in a particular geographic region (in this instance in the provinces of Groningen and Friesland). However, the typical ECG characteristics were later recognised in other parts of the country and these patients appeared to be descendants from the same ancestors and to carry the same mutation. In the last decade we have performed several clinical and preclinical studies in the family carrying the
SCN5a 1795insD mutation and in mice carrying a homologue mutation (
SCN5a 1798insD).
1–14 In this part of a series on founder mutations in the Netherlands we review what we have learned from these studies and look forward to more insights into the observed variability in this arrhythmia syndrome and possibly also in other populations. …
