Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community

Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone

<p>Abstract</p> <p>Background</p> <p>The effect of neurotrophic factors in enhancing stroke-induced neurogenesis in the adult subventricular zone (SVZ) is limited by their poor blood-brain barrier (BBB) permeability.</p> <p>Intranasal administration is a noninvasive and valid method for delivery of neuropeptides into the brain, to bypass the BBB. We investigated the effect of treatment with intranasal transforming growth factor-β1 (TGF-β1) on neurogenesis in the adult mouse SVZ following focal ischemia. The modified Neurological Severity Scores (NSS) test was used to evaluate neurological function, and infarct volumes were determined from hematoxylin-stained sections. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling was performed at 7 days after middle cerebral artery occlusion (MCAO). Immunohistochemistry was used to detect bromodeoxyuridine (BrdU) and neuron- or glia-specific markers for identifying neurogenesis in the SVZ at 7, 14, 21, 28 days after MCAO.</p> <p>Results</p> <p>Intranasal treatment of TGF-β1 shows significant improvement in neurological function and reduction of infarct volume compared with control animals. TGF-β1 treated mice had significantly less TUNEL-positive cells in the ipsilateral striatum than that in control groups. The number of BrdU-incorporated cells in the SVZ and striatum was significantly increased in the TGF-β1 treated group compared with control animals at each time point. In addition, numbers of BrdU- labeled cells coexpressed with the migrating neuroblast marker doublecortin (DCX) and the mature neuronal marker neuronal nuclei (NeuN) were significantly increased after intranasal delivery of TGF-β1, while only a few BrdU labeled cells co-stained with glial fibrillary acidic protein (GFAP).</p> <p>Conclusion</p> <p>Intranasal administration of TGF-β1 reduces infarct volume, improves functional recovery and enhances neurogenesis in mice after stroke. Intranasal TGF-β1 may have therapeutic potential for cerebrovascular disorders.</p

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms

Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genetic association study of childhood aggression across raters, instruments, and age

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis AGGoverall was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations rg among rater-specific assessment of AGG ranged from rg= 0.46 between self- and teacher-assessment to rg= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg=∼-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.</p

The diagnostic ability of pediatric transthoracic echocardiography in the current era : a segmental appraisal

Includes bibliographical references (leaves 19-21).Transthoracic echocardiography (TTE) plays a crucial role in the care of pediatric patients with heart disease. However, despite numerus recent technological advances, there has been little re-assessment of its accuracy. We sought to systematically assess the diagnostic accuracy of pediatric TTE in the current era

Burnout and work-life balance among paediatric cardiologists

Recording of presentation given by William L. Border with the title 'Burnout and work-life balance among paediatric cardiologists', presented on Friday, 15 March 2019 as part of the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop in Cape Town, South Africa.The 13th-16th March 2019 marked the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop hosted by the Children’s Heart Disease Research Unit under the directorship of A/Prof Liesl Zuhlke and in conjunction with the Paediatric Cardiology Service of the Western Cape. A first in Africa, this workshop combined four events: a research methods workshop, a basic echocardiography (echo) workshop, two days of advanced echo as well as a rheumatic heart disease research think-tank. 130 delegates from 19 different countries representing all six continents attended the event, making it truly global and giving attendees the opportunity to meet and network with experts in the fields of rheumatic and congenital heart disease.</div

Exercise stress echocardiography: Utility in paediatric and adult patients with congenital heart disease

Recording of presentation given by William L. Border with the title 'Exercise stress echocardiography: Utility in paediatric and adult patients with congenital heart disease', presented on Friday, 15 March 2019 as part of the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop in Cape Town, South Africa.The 13th-16th March 2019 marked the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop hosted by the Children’s Heart Disease Research Unit under the directorship of A/Prof Liesl Zuhlke and in conjunction with the Paediatric Cardiology Service of the Western Cape. A first in Africa, this workshop combined four events: a research methods workshop, a basic echocardiography (echo) workshop, two days of advanced echo as well as a rheumatic heart disease research think-tank. 130 delegates from 19 different countries representing all six continents attended the event, making it truly global and giving attendees the opportunity to meet and network with experts in the fields of rheumatic and congenital heart disease.</div

Echo approach to heterotaxy

Recording of presentation given by William L. Border with the title 'Echo approach to heterotaxy', presented on Friday, 15 March 2019 as part of the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop in Cape Town, South Africa.The 13th-16th March 2019 marked the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop hosted by the Children’s Heart Disease Research Unit under the directorship of A/Prof Liesl Zuhlke and in conjunction with the Paediatric Cardiology Service of the Western Cape. A first in Africa, this workshop combined four events: a research methods workshop, a basic echocardiography (echo) workshop, two days of advanced echo as well as a rheumatic heart disease research think-tank. 130 delegates from 19 different countries representing all six continents attended the event, making it truly global and giving attendees the opportunity to meet and network with experts in the fields of rheumatic and congenital heart disease.</div

Atrio-ventricular septal defects

Recording of presentation given by William L. Border with the title 'Atrio-ventricular septal defects', presented on Wednesday, 13 March 2019 as part of the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop in Cape Town, South Africa.The 13th-16th March 2019 marked the Inaugural PROTEA (Partnerships for Children with Heart Disease in Africa) Workshop hosted by the Children’s Heart Disease Research Unit under the directorship of A/Prof Liesl Zuhlke and in conjunction with the Paediatric Cardiology Service of the Western Cape. A first in Africa, this workshop combined four events: a research methods workshop, a basic echocardiography (echo) workshop, two days of advanced echo as well as a rheumatic heart disease research think-tank. 130 delegates from 19 different countries representing all six continents attended the event, making it truly global and giving attendees the opportunity to meet and network with experts in the fields of rheumatic and congenital heart disease.</div