A genetic investigation into inherited ventricular arrhythmias

Inherited ventricular arrhythmias are important because a) it can cause sudden cardiac death b) affected patients are often young and c) it causes great anxiety on the family members. An understanding of the genetic factors that contribute to inherited ventricular arrhythmias may help in risk- stratification. This study focussed on two large Caucasian families. The proband in family A presented with cardiac arrest secondary to a ventricular tachyarrhythmia and an abnormal ECG. Similar ECGs were documented in 6 other members in family A, over 3 generations, and they were further identified by electrophysiological tests to be at high risk of ventricular arrhythmias. The proband in family B presented with syncope. There was strong family history of sudden death and syncope. The resting ECGs were within normal limits. Electrophysiological testing identified 3 family members to be at high risk of ventricular arrhythmias. Standard investigations showed affected subjects to have structurally normal hearts. The clinical characteristics did not fit with known conditions associated with sudden death in a structurally normal heart. It was therefore hypothesised that mutations in a novel gene or novel mutations in a previously identified gene caused the phenotype. The aim was to exclude 8 candidate genes by genotyping and pedigree analysis. If any gene could not be excluded, the aim was to investigate it further. If all 8 genes were excluded, the aim was to perform a genome wide scan to identify the locus in the genome likely to harbour the gene of interest. DNA was available on 7 affected subjects in family A and 5 affected subjects in family B. Following genotyping, 6 out of 8 genes were excluded. TNNT2 and RyR2, both located on the long arm of chromosome 1, could not be excluded in family A. RyR2 and ANKB could not be excluded in family B. TNNT2 was prioritised for mutation screening. Direct sequencing of the coding exons of TNNT2 and the intron-exon boundaries identified sequence variations in two subjects but did not demonstrate a common variation in all the affected subjects. In conclusion, it is likely that the mutated gene in family A is located at lq. However, the genetic cause for the phenotype in the two families remains unknown and further investigations are required to identify this.