Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors.

Background: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging.

Objectives: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors.

Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure.

Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.

Purpose: The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.

Methods: Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD.

High throughput exome coverage of clinically relevant cardiac genes.

Background: Given the growing use of whole-exome sequencing (WES) for clinical diagnostics of complex human disorders, we evaluated coverage of clinically relevant cardiac genes on WES and factors influencing uniformity and depth of coverage of exonic regions.

Methods: Two hundred and thirteen human DNA samples were exome sequenced via Illumina HiSeq using different versions of the Agilent SureSelect capture kit. 50 cardiac genes were further analyzed including 31 genes from the American College of Medical Genetics (ACMG) list for reporting of incidental findings and 19 genes associated with congenital heart disease for which clinical testing is available.

Identification of deleterious synonymous variants in human genomes.

Motivation: The prioritization and identification of disease-causing mutations is one of the most significant challenges in medical genomics. Currently available methods address this problem for non-synonymous single nucleotide variants (SNVs) and variation in promoters/enhancers; however, recent research has implicated synonymous (silent) exonic mutations in a number of disorders.

Results: We have curated 33 such variants from literature and developed the Silent Variant Analyzer (SilVA), a machine-learning approach to separate these from among a large set of rare polymorphisms.

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.

Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype.

Background: Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigated the association of variants in hypoxia-response genes with phenotype severity in pediatric HCM.

Methods: A total of 80 unrelated patients <21 y and 14 related members from eight families with HCM were genotyped for six variants associated with vascular endothelial growth factor A (VEGFA) downregulation, or hypoxia-inducible factor A (HIF1A) upregulation.

Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair.

Background: Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair.

Methods: Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A.

Personalized Medicine in the Genomics Era: highlights from an international symposium on childhood heart disease.

As the population of childhood heart disease survivors grows, a better understanding of the genetic underpinnings of heart disease is needed to improve diagnostics, therapeutics and outcomes. The Trans-Atlantic Research Network, GenomeHeart and The SickKids Heart Centre Biobank hosted an international symposium on childhood heart disease titled 'Personalized Medicine in the Genomics Era'. Experts in cardiology, developmental biology, genomics, pharmacology, bioinformatics, stem cell biology, ethics and biobanking shared their knowledge and expertise.

Cardiac Troponin T (TNNT2) mutations are less prevalent in Indian hypertrophic cardiomyopathy patients.

We sought to determine the frequency of the genetic variations in the Troponin T (TNNT2) gene and its association in Indian cardiomyopathy patients. Sequencing of the entire TNNT2 gene in 162 hypertrophic cardiomyopathy (HCM) patients, along with 179 healthy controls, revealed a total of 15 variants. These included an A28V missense mutation, a novel single-nucleotide polymorphism (SNP) (g.

Differential expression of TNF-α signaling molecules and ERK1 in distal and proximal colonic tumors associated with obesity.

Distal and proximal colon cancers have been recognized as two different disease types in human population. The environmental factors involved in the pathogenesis of the proximal and distal tumors also differ. The main objective of this study was to determine if obesity-augmented colonic tumors differ from each other if they are located in different regions of the colonic axis.

Haplotypes on 9p21 modify the risk for coronary artery disease among Indians.

The chromosomal region 9p21 has been reported to be associated with myocardial infarction, coronary artery disease (CAD), diabetes, and many other related multifactorial diseases in humans. Although the genome-wide association studies have identified a limited number of single-nucleotide polymorphisms (SNPs) at 9p21 for CAD risk, the role of flanking SNPs has not been studied so far. Therefore, in the present work, we studied the role of flanking SNPs with respect to that of the previously identified SNPs rs10757278 and rs2383207 at 9p21 among the Indian subjects found to have CAD (n = 414) along with age- and sex-matched control subjects (n = 408).

Associations for lipoprotein lipase and peroxisome proliferator-activated receptor-gamma gene and coronary artery disease in an Indian population.

Background And Aims: Peroxisome proliferator activated receptor-gamma (PPARgamma) and lipoprotein lipase (LPL) genes are important in pathways of triglyceride metabolism, insulin resistance and adipogenesis. We hypothesized that polymorphisms of PPARgamma Pro12Ala, LPL HindIII and LPL Ser447X influence severity of coronary artery disease (CAD) in an Indian population.

Methods: PPARgamma Pro12Ala, LPL HindIII and LPL Ser447X polymorphisms were genotyped in 414 patients with CAD and matched with 424 controls.

Genetic variants on apolipoprotein gene cluster influence triglycerides with a risk of coronary artery disease among Indians.

Apolipoprotein C3 and apolipoprotien A5 are proteins coded from the APOA1/C3/A4/A5 gene cluster. Sst I polymorphism on apolipoprotein C3 and -1131C polymorphism of apolipoprotien A5 are key variants involved in triglyceride metabolism and cause a significant cardio-metabolic risk. Here, we have evaluated these two variants for their roles in coronary artery disease in patients of the Indian population.