The role of molecular genetics in the diagnoses of sudden arrhythmic death syndromes in New Zealand

Abstract

Inherited cardiac arrhythmias are leading causes of death and disability. The cardiac channelopathies, of which long QT syndrome (LQTS) is most common, are a heterogenous group of disorders of cardiac ion channels that can cause sudden unexplained death in up to 80, otherwise healthy, young New Zealanders each year. LQTS is characterised by recurrent syncope (fainting), seizure and sudden death. Clinical diagnosis can be challenging and therapeutic intervention often depends on the gene responsible. Therefore, it is important to obtain a molecular diagnosis wherever possible to establish preventative clinical best-practice. The Cardiac Inherited Disease Group (CIDG) is a multidisciplinary group that aims to save the lives and support the families of children and young adults who have inherited cardiac arrhythmia syndromes. This study forms part of the research arm of the CIDG. To identify and assess the frequency and spectrum of LQTS associated mutations, both clinically diagnosed LQTS families and a sudden unexpected death cohort were screened for mutations in the five LQTS genes using denaturing high performance liquid chromatography (dHPLC) and direct sequencing. The mutation detection rate was 52%. To investigate the molecular genetic cause of LQTS symptoms in the remaining mutation-negative cohort, multiplex ligation-dependent probe amplification and comparative genomic hybridization arrays were used to investigate copy number variation in LQTS-associated genes. Altered exon copy number was detected in 3 (11.5%) patients: (1) a KCNQ1 exon 13-14 deletion (2) a KCNH2 exon 6-14 deletion and (3) a KCNH2 exon 9-14 duplication, suggesting that sequencing-based mutation detection strategies should be followed by deletion/duplication screening in all LQTS mutationnegative patients. As catecholaminergic polymorphic ventricular tachycardia (CPVT) presents similarly to LQTS, the CPVT-associated cardiac ryanodine receptor gene (RYR2) was screened for mutations using direct sequencing. Five RYR2 variants were detected among the LQTS mutation-negative cases. Lastly, a selection of unclassified variants or single nucleotide polymorphisms (SNPs) were typed using Taqman genotyping assays as a pilot study to investigate their role as potential susceptibility loci or genetic modifiers of established mutations. No significant associations were identified. However, certain trends worth following up in a larger cohort were noted. Although the genetic cause of arrhythmia symptoms has been established in nine mutation-negative index cases, further studies using different strategies are required to establish the genetic cause in a greater proportion of mutation-negative cases.