Over the last couple of years, there have been a lot of publications underlining the importance of genetic testing in cardiac disorders. The careful curation of genes improves establishing diagnosis.
Focus on the TECRL gene
Recently, Devalla et al. described TECRL as a new life-threatening inherited arrhythmia gene associating with clinical features overlapping with both long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT)1, causing high risk for sudden cardiac death.
“The TECRL gene should become available for testing of inherited arrhythmias at a large scale to gain full benefit from the latest discovery and help establishing diagnosis in as many cases as possible,” urges Blueprint Genetics’ Executive Director of Medical & Lab Director Juha Koskenvuo.
This study published, by EMBO Molecular Medicine, is considered one of the major discoveries of the decade in the field of chanellopathies. It was also acknowledged by Perry and Vandenberg2 in the same issue’s editorial.
Quality over quantity
When panels become larger, in some cases, the evidence gets weaker. There can be many genes of uncertain significance (GUS) within NGS panels. What is meant by ‘GUS’ is that there are a lot of genes that were initially shown to be linked to arrhythmias and cardiomyopathies, but if you look really carefully at the evidence with today’s standards, the evidence is actually quite weak. This is mainly based on the fact that older publications identified variants in patients that are actually quite common in the general population, which was uncovered when ExAc and gnomAD browsers were made available.
“As we gain more information and gather further population data, we see that most of the variations within the GUS genes are not disease causing although initially interpreted as such,” Koskenvuo says.
According to Koskenvuo, it is extremely important to focus on the relevance rather than a panel’s number of genes.
“Comprehensive panels without relevance makes it just more confusing for both the clinical interpretation process and the clinician. A recent study from Giudicessi et al3 references to weak evidence genes in the genetic diagnostics of LQTS, underlining the importance of relevance,” he continues.
In short: Long QT syndrome (LQTS)
Long QT syndrome (LQTS) can present as unexpected fainting, ventricular arrhythmias, and sudden cardiac death in patients with structurally normal hearts. Sudden death is the first symptom in 10%-15% of long QT syndrome patients. The prevalence of LQTS is estimated to be 1:3000.
“Genetic testing is an increasingly important component for the evaluation of LQTS patients. Disease-causing mutations in genes encoding cardiac ion-channels can be detected in up to 40%-75% of patients with a clinical diagnosis of LQTS. Additionally, genetic testing may be the only way to identify at risk family members,” Koskenvuo concludes.
In short: TECRL
This gene associates with a severe phenotype and is related to LQTS/CPVT related calmodulin genes, CALM1, CALM2, CALM3, but the phenotype is recessive in TECRL. In light of latest research, Blueprint Genetics added the gene to Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Panel and Long QT Syndrome (LQTS) Panel, Arrhythmia Panel and Comprehensive Cardiology Panel.
See our cardiology panels here.
- TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. https://www.ncbi.nlm.nih.gov/pubmed/27861123
- TECRL: connecting sequence to consequence for a new sudden cardiac death gene. https://www.ncbi.nlm.nih.gov/pubmed/27784710
- The genetic architecture of long QT syndrome: A critical reappraisal. https://www.ncbi.nlm.nih.gov/pubmed/29661707