Large next-generation sequencing gene panels in genetic heart disease: challenges in clinical practice.

I Christiaans,R H Lekanne Dit Deprez,M Alders,O R F Mook,H Bikker

doi:10.1007/s12471-019-1251-4

Abstract

BackgroundNext-generation sequencing gene panels are increasingly used for genetic diagnosis in inherited cardiac diseases. Besides pathogenic variants, multiple variants, variants of uncertain significance (VUS) and incidental findings can be detected. Such test results can be challenging for counselling and clinical decision making.MethodsWe present patient cases to illustrate the challenges that can arise when unclear genetic test results are detected in cardiogenetic gene panels.ResultsWe identified three types of challenging gene panel results: 1) one or more VUS in combination with a pathogenic variant, 2) variants associated with another genetic heart disease, and 3) variants associated with a syndrome involving cardiac features.ConclusionLarge gene panels not only increase the detection rates of pathogenic variants but also of variants with uncertain pathogenicity, multiple variants and incidental findings. Gene panel results can be challenging for genetic counselling and require proper pre-test and post-test counselling. We advise evaluation of challenging cases by a multidisciplinary team.

Highlights

In inherited cardiac diseases next-generation sequencing (NGS) techniques with sequencing and analysis of multiple genes in a single experiment have become standard diagnostic care [1]
Identified class 1 and 2 variants are not reported to the requesting physician. Both genetic counsellors and patients were aware of the possibility of variants of uncertain/unknown significance (VUS) detection and associated uncertainty, they encountered challenges in counselling and clinical decision making in some patients
We describe three types of challenges in counselling/clinical decision making derived from the gene panel results

Summary

Introduction

In inherited cardiac diseases next-generation sequencing (NGS) techniques with sequencing and analysis of multiple genes in a single experiment have become standard diagnostic care [1]. Testing more genes using a gene panel or other NGS-based technique increases the detection rate of disease-causing variants, and of variants of uncertain/unknown significance (VUS). With the more frequent use of NGS, genetic counsellors are increasingly being confronted with VUS. Next-generation sequencing gene panels are increasingly used for genetic diagnosis in inherited cardiac diseases. Multiple variants, variants of uncertain significance (VUS) and incidental findings can be detected. Such test results can be challenging for counselling and clinical decision making

Methods

Results

Conclusion