Arrhythmias caused by congenital or acquired abnormalities of cardiac K+ or Na+ channels are increasingly recognized as a cause of syncope and sudden death. Cardiac arrest in the absence of overt structural heart disease was previously considered idiopathic ventricular fibrillation (IVF). The list of causes of ”unexplained” cardiac arrest (UCA) now encompasses K+ related abnormalities (Long and Short QT, Andersen's), Na+ related (Long QT3, Brugada), Ca++ related (Catecholaminergic Polymorphic Ventricular Tachycardia-CPVT), and latent cardiomyopathy. These underlying causes of cardiac arrest are overtly familial in 30-60% of cases. Clinical detection of the underlying phenotype is crucial to direct appropriate treatment, genetic testing and screening of family members.

Phenotype recognition of the range of these rare genetic conditions includes non-invasive and invasive testing to demonstrate the hallmarks of each individual condition, and exclude common causes such as ischemic or idiopathic forms of cardiomyopathy. The outcomes from this type of testing have not been assessed in a systematic fashion in patients with UCA or their family members. Phenotype-genotype correlation is necessary to develop optimal diagnostic testing in probands and screening techniques in their family members, which will result in disease-specific therapy. Genetic testing of patients with an overt phenotype demonstrates a potentially causative mutation in 50-75% of LQTS patients, and 20% of Brugada's Syndrome patients.

Despite recognized mutations with phenotypic expression models, 30-80% of patients will have negative gene screening despite overt or latent clinical disease.

The proposed project will evaluate a systematic approach to clinical assessment and genetic screening of patients and families with UCA and suspected inherited arrhythmias involving:

1. A multicenter registry of UCA patients, their family members and referred patients with familial sudden death undergoing standardized testing for evidence of primary electrical disease (PED). The single center pilot experience at the applicant's institution has proven feasibility, and has been accepted for publication in Circulation, indicating novelty. Six centers have agreed to participate, with enrollment in 2 underway, 2 centers with Ethics approval beginning enrollment, and 2 further in the submission process. The target is to enroll 50 UCA probands, 100 family members and 50 1st degree relatives of autopsy negative unexplained sudden death victims.
2. DNA testing of affected individuals involving testing for LQTS, Brugada's Syndrome and CPVT. This project will partner with Dr. Michael Gollob at University of Ottawa for DNA sequencing.