In recent years the principal investigators and participators in this project have started to collect DNA samples of patients and families with (potentially) inherited cardiac diseases associated with cardiac arrhythmias. ICIN has greatly facilitated the logistics of these efforts, both on 1) the level of DNA sampling and 2) of the molecular genetic analysis of several syndromes.
ad 1) Completion of families of interest is an ongoing effort made feasible by the ICIN-granted research nurse who travels around the country to obtain ECGs and DNA in the out-hospital setting.
ad 2) In families with primary arrhythmia syndromes (LQTS and idiopathic VF) new mutations have been found and specific genotype-phenotype relationships have been established. Thus far 6 genetic loci (5 genes) have been identified in patients with LQTS, and one gene has been linked to idiopathic VF. Insight into the pathophysiology of these syndromes is achieved by studying the electrophysiological characteristics of wild-type and mutated ion channels in heterologous expression systems.
A more frequent cardiac disorder associated with malignant arrhythmias is hypertrophic cardiomyopathy (HCM), equally identified as a genetically heterogeneous disorder with current identification of 9 genes. For practical reasons it is not yet possible to screen all genes for all familial cases. Therefore, a protocol was developed to search specifically for those mutations, which are associated with a high incidence of sudden cardiac death (SCD). The presence of such a mutation will allow presymptomatic investigations in the family of the patient and the identification of relatives with and without the genetic risk. Families with SCD were selected and tested for mutations in part of the beta-myosin heavy chain (MHC) and the troponin-T gene. Mutations in the troponin-T gene are specifically associated with a severe phenotype and a mild or absent hypertrophy. About 50% of all HCM mutations can be expected in these two genes. In the troponin-T gene, however, only one mutation was found (Lys253Arg substitution), whereas in the beta-MHC gene 9 mutations were found in a total of 60 families. Seven of these mutations were identified in the last 2 years during the course of the ICIN project. Although families were selected on SCD, also mutations were identified, which were reported to be mild in literature. This indicates that although the characterized mutations enable family investigations and the identification of individuals at risk, care has to be taken with respect to prognostic predictions of these findings. Mutation analysis in part of the cardiac troponin-T gene has also been performed in patients with unexplained cardiac arrest and no or mild cardiac hypertrophy. In general, the necessity for this type of studies has been addressed. |
