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Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry
- Source :
- PloS one, vol 13, iss 11, PLoS ONE, PLoS ONE, Vol 13, Iss 11, p e0205925 (2018)
- Publication Year :
- 2018
- Publisher :
- Public Library of Science (PLoS), 2018.
-
Abstract
- Author(s): Roston, Thomas M; Haji-Ghassemi, Omid; LaPage, Martin J; Batra, Anjan S; Bar-Cohen, Yaniv; Anderson, Chris; Lau, Yung R; Maginot, Kathleen; Gebauer, Roman A; Etheridge, Susan P; Potts, James E; Van Petegem, Filip; Sanatani, Shubhayan | Abstract: BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants.MethodsThe phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics a Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state).ResultsAmong 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign.ConclusionsThis severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.
- Subjects :
- Male
0301 basic medicine
Physiology
lcsh:Medicine
Pathogenesis
030204 cardiovascular system & hematology
Pathology and Laboratory Medicine
Cardiovascular
Biochemistry
Ion Channels
0302 clinical medicine
Heart Rate
Tachycardia
Medicine and Health Sciences
2.1 Biological and endogenous factors
Registries
Aetiology
lcsh:Science
Child
Pediatric
education.field_of_study
Multidisciplinary
medicine.diagnostic_test
Physics
Genomics
Penetrance
3. Good health
Electrophysiology
Heart Disease
Treatment Outcome
Child, Preschool
Physical Sciences
Medical genetics
Female
medicine.symptom
Ion Channel Gating
Arrhythmia
Research Article
medicine.medical_specialty
Substitution Mutation
Adolescent
General Science & Technology
Genetic counseling
Population
Biophysics
Cardiology
Neurophysiology
Catecholaminergic polymorphic ventricular tachycardia
Syncope
03 medical and health sciences
Signs and Symptoms
Rare Diseases
Genomic Medicine
Protein Domains
Diagnostic Medicine
Internal medicine
Genetics
medicine
Humans
Genetic Predisposition to Disease
Genetic Testing
Expressivity (genetics)
Preschool
education
Genetic testing
Clinical Genetics
business.industry
Myocardium
lcsh:R
Human Genome
Infant, Newborn
Ventricular
Biology and Life Sciences
Proteins
Infant
Human Genetics
Ryanodine Receptor Calcium Release Channel
Sudden cardiac arrest
Newborn
medicine.disease
030104 developmental biology
Mutation
Tachycardia, Ventricular
lcsh:Q
business
Neuroscience
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....b785e5b6cd5582bccf4c782c8d42bf9e