Copy Number Variants in Cardiac Channelopathies: Still a Missed Part in Routine Arrhythmic Diagnostics

Abstract

Inherited cardiac channelopathies are major causes of sudden cardiac death (SCD) in young people. Genetic testing is focused on the identification of single-nucleotide variants (SNVs) by Next-Generation Sequencing (NGS). However, genetically elusive cases can carry copy number variants (CNVs), which need specific detection tools. We underlie the utility of identifying CNVs by investigating the literature data and internally analyzing cohorts with CNVs in KCNQ1, KCNH2, SCN5A, and RYR2. CNVs were reported in 119 patients from the literature and 21 from our cohort. Young patients with CNVs in KCNQ1 show a Long QT (LQT) phenotype > 480 ms and a higher frequency of syncope. None of them had SCD. All patients with CNV in KCNH2 had a positive phenotype for QT > 480 ms. CNVs in SCN5A were represented by the Brugada pattern, with major cardiac events mainly in males. Conversely, adult females show more supraventricular arrhythmias. RYR2-exon3 deletion showed a broader phenotype, including left ventricular non-compaction (LVNC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Pediatric patients showed atrial arrhythmias and paroxysmal atrial fibrillation. Relatively higher syncope and SCA were observed in young females. The detection of CNVs can be of greater yield in two groups: familial channelopathies and patients with suspected Jervell and Lange-Nielsen syndrome or CPVT. The limited number of reported individuals makes it mandatory for multicentric studies to give future conclusive results.

Keywords: Brugada; catecholaminergic polymorphic ventricular tachycardia; channelopathies; copy number variants; long QT.

Figure 1

Method used to conduct the literature search for this study.

Figure 2

Graphical overview of current knowledge of major steps in genetic testing in patients with ICAs. The figure includes details on CNV testing, literature data, and results from this study.

Figure 3

Family pedigrees of the described cohort of 21 individuals with CNV in one of the analyzed genes of cardiac channelopathies. From top to bottom: KCNQ1, SCN5A, and RYR2 gene deletion. Phenotypic and genotypic features of probands and their relatives are shown according to the legend on the lower right of the figure. All CNVs are heterozygous unless otherwise specified. JLNS: Jervell and Lange-Nielsen syndrome. HT: hypertrabeculation. LVNC: left ventricular non-compaction. CPVT: catecholaminergic polymorphic ventricular tachycardia.

Figure 4

Detection of CNVs involving arrhythmic genes identified by P114 and P108 MRC Holland MLPA kits. The relative peak ratio of MLPA products in these profiles reflects the presence of exon deletions or duplications compared with reference samples. Blue/green bars represent a 95% confidence interval over the reference samples (N = 4), and dots with lines represent a 95% confidence interval estimate for each probe. The chromosomal positions and bands in the MLPA kits are all based on the hg18 genome; we convert the genomic coordinates to hg19 according to the CNVs described in the literature. For this reason, The NM_ sequence used by the company to determine a probe’s ligation site does not always correspond to the exon numbering obtained from the LRG sequences (Locus Reference Genomic). (A,B) We identified different KCNQ1 deletions in 4 unrelated families. (A) Patient 1 shows a single copy loss of exon 1 in KCNQ1 transcript variant 2 (NM_181798.1). (B) In patient 35, we identified a homozygous deletion of KCNQ1 exon 16. (C) Deletion in SCN5A gene.