A validated heart-specific model for splice-disrupting variants in childhood heart disease.

Background: Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests.

Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy.

Background: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood.

Objectives: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients.

An Integrated Clinical and Genetic Prediction Model for Tacrolimus Levels in Pediatric Solid Organ Transplant Recipients.

Background: There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study was to generate an integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT.

Methods: In a multicenter prospective observational cohort study (2015-2018), children <18 years old at their first SOT receiving tacrolimus as maintenance immunosuppression were included (455 as discovery cohort; 322 as validation cohort).

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies.

Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible.

Return of genetic and genomic research findings: experience of a pediatric biorepository.

Background: Assess process, uptake, validity and resource needs for return of actionable research findings to biobank participants.

Methods: Participants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor.

Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy (POSITIVE Study): The Collaboration and Design of a National Transplant Precision Medicine Program.

Background: Despite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults.

A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation.

Background: Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied.

Objective: To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations.

Personalized medicine in the care of the child with congenital heart disease: discovery to application.

On October 27-28, 2012, the SickKids Labatt Family Heart Centre and the Heart Centre Biobank Registry hosted the second international GenomeHeart symposium in Toronto, Ontario. The symposium featured experts in cardiology, developmental biology, pharmacology, genomics, bioinformatics, stem cell biology, biobanking, and ethics. The theme of this year's symposium was the application of emerging technologies in genomics, proteomics, transcriptomics, and bioinformatics to diagnostics and therapeutics of the child with heart disease.

Factors influencing participation in a population-based biorepository for childhood heart disease.

Background: Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease.

Methods: Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form.