Authors:

LB Bidina¹ , D Rots¹ , L Caunite² , K Kupics² , O Kalejs² , L Gailite¹ , ¹Riga Stradins University - Riga - Latvia , ²Paul Stradins Clinical University Hospital - Riga - Latvia ,

Citation:

Introduction

Genetic testing for arrythmogenic right ventricular cardiomyopathy (ARVC) has significantly increased in the last years. Whole exome and genome sequencing (WES) have expanded the possible genetic background of the ARVC – now 19 genes are described.  Genotype and phenotype overlap are seen more frequently between different cardiomyopathies and channelopathies.

Purpose

The aim of this study was to analyze genetic variations in 19 genes which are associated with ARVC phenotype, using of next-generation sequencing (NGS).

Methods

NGS using TruSight One kit was done for 24 ARVC patients. Sentieon software was used for variant calling and the duplicate removal. wAnnovar softwares was used to variants’ annotation. GRCh38 and RefSeq transcripts were used for read alignment and variant annotation. The mean coverage was 70x and 93% of target region was sequenced at coverage at least 20x. 19 genes, which are associated with ARVC, were analyzed - PKP2, DSG2, DSC2, JUP, PLN, LMNA, SCN5A, CTNNA3, TGFB3, RYR2, TTN, TMEM43, DES, DSP, FLNC, LDB3, CDH2, TGFB3, TP63. Additionally large deletions and duplication were analyzed by MLPA analysis. Interpretation of genetic variants were done based on ACMG[LP4] erican College of Medical Genetics guidelines.

Results

One pathogenic splice site variation (rs111517471) was found for one patient in PKP2 gene, one likely pathogenic stopgain variation (rs775072385) was found for one patient in TTN gene. One likely pathogenic missense variation (rs147240502) was found for one patient in PKP2 gene, for the first time discovered in the homozygote form and inherited in autosomal recessive trait. Seven different variants of uncertain significance were found in genes DSG2, DSP, SCN5A, RYR2, CTNNA3 and DES. No large deletions nor duplication were found by MLPA analysis.

Conclusion

By performing whole exome sequencing and analyzing 19 ARVC associated genes, only for three out of 24 patients pathogenic or likely pathogenic variations were found. It is clearly seen that separated gene panels are not sufficient for diagnostic purposes of ARVC. In our opinion WES should always be performed for ARVC patients, and analysis of wide cardiology associated genes’ panel should be done. The next step of our study will be an expanded cardiology associated gene panel analysis for ARVC patients.