Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

Abstract

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; “uncommon genes”). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype.

An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs

“…There are greater than 70 candidate genes for sudden cardiac death and greater than 40 for nonsyndromic DCM, but many lack definitive evidence to confirm their role in these diseases [10,11]. A study on results of panel testing of more than 200 genes in patients with inherited cardiomyopathies or channelopathies found that 61% of variants detected resided in genes with insufficient evidence to confirm disease association, and 70% of those were variants of unknown significance [64]. Data from dogs and other natural animal models of sudden cardiac death and DCM can contribute to evidence of gene associations with disease and variant pathogenicity and thereby hold value in improving the accuracy of molecular autopsies.…”

Desmosomes in heart and skin: friends or foes?

“…Therefore, the aim of the current research is to investigate the presence of dermatological alterations in ACM patients carrying mutations in desmosomal genes. Patients (both sexes, age > 18 years) with a definite, borderline, or possible ACM diagnosis underwent molecular genetic testing, conducted at CEINGE_ Advanced Biotechnology Franco Salvatore of Naples, by analysing a panel of more than 100 genes associated with hereditary cardiomyopathies [ 3 , 4 ]. 14 ACM patients carrying one or more variants in desmosomal genes agreed to carry out a dermatological check-up, at the Section of Dermatology of the University of Naples Federico II.…”

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

“…Focused on genes associated with IAS (no more than 20 major genes -ACTC1, DSC2, DSG2, DSP, HCN4, FLNC, KCNH2, KCNQ1, LMNA, MYBPC3, MYH7, PKP2, PLN, RyR2, SCN5A, TNNI3, and TTN-, and no more than 100, including minor ones) (7), the technical approach to screen a large number of genes is not the limitation to date. It is widely accepted that increasing the number of genes imply a greater number of rare variants, remaining the most part without a conclusive role in IAS; however, a recent study has suggested that combined cardiomyopathy and arrhythmia genetic testing is able to identify a 10.9% gain in genetic diagnoses that would have been missed if testing had been limited to genes associated with a single cardiomyopathy or arrhythmia panel of genes (79,80). If clinical evaluation is included in genetic diagnosis, the diagnostic yield of molecular autopsy increases to nearly 35% (81).…”