The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele.

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect.

A Functional Assay for Sick Sinus Syndrome Genetic Variants.

Background/aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants.

Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events.

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families.

Kawasaki Disease and Exposure to Fine Particulate Air Pollution.

Objective: To analyze associations of short-term exposure to fine particulate matter (diameter ≤ 2.5 µm [PM2.5]), a measurable component of urban pollution, with the event date of fever onset for patients with Kawasaki disease (KD) residing in 7 metropolitan regions.

Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.

Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing.

Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR).

Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left-right development. Previously, we reported causative links between TAVPR and the PDGFRA gene.

Novel mutation in the α-myosin heavy chain gene is associated with sick sinus syndrome.

Background: Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. Moreover, a rare MYH6 variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing MYH6 mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown.

The role of screening and prophylactic surgery for malrotation in heterotaxy patients.

Purpose: There are no standardized guidelines for screening or management of malrotation in Heterotaxy Syndrome (HS). We sought to review our experience to determine if evidenced based guidelines could be drafted.

Methods: A retrospective chart review was performed at our freestanding children's hospital on all patients under one year of age undergoing a Ladd procedure between 2000 and 2011.

Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants.

Objective: Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association.

Neonatal flail tricuspid valve: diagnosis and management.

Flail tricuspid valve in the neonate is a rare and often fatal condition requiring early diagnosis and intervention. We report 3 infants born without antenatal signs of cardiovascular compromise. Severe hypoxemia developed within hours of birth due to disruption of the anterior leaflet of the tricuspid valve.

White matter lesions in children and adolescents with migraine.

Background: The etiology and clinical importance of white matter lesions in migraine remain poorly understood. To understand these issues more fully, we reviewed the brain magnetic resonance imaging scans of pediatric patients and assessed the relationships between white matter lesions, migraine type, patent foramen ovale, and right-to-left shunting.

Methods: The magnetic resonance imaging scans of a cohort of children (n = 89) and adolescents, ages 6 to 18 years, who participated in a study of migraine and patent foramen ovale were reviewed.

Sdc2 and Tbx16 regulate Fgf2-dependent epithelial cell morphogenesis in the ciliated organ of asymmetry.

Heparan sulfate proteoglycans (HSPGs) control many cellular processes and have been implicated in the regulation of left-right (LR) development by as yet unknown mechanisms. Using lineage-targeted knockdowns, we found that the transmembrane HSPG Syndecan 2 (Sdc2) regulates LR patterning through cell-autonomous functions in the zebrafish ciliated organ of asymmetry, Kupffer's vesicle (KV), including regulation of cell proliferation and adhesion, cilia length and asymmetric fluid flow. Exploring downstream pathways, we found that the cell signaling ligand Fgf2 is exclusively expressed in KV cell lineages, and is dependent on Sdc2 and the transcription factor Tbx16.

Family-based studies to identify genetic variants that cause congenital heart defects.

Congenital heart defects (CHDs) are the most common congenital abnormalities. Analysis of large multigenerational families has led to the identification of a number of genes for CHDs. However, identifiable variations in these genes are the cause of a small proportion of cases of CHDs, suggesting significant genetic heterogeneity.

Heterotaxy syndrome: impact of ventricular morphology on resource utilization.

Patients with heterotaxy syndrome (HS) have significant cardiac and extracardiac anomalies that impact outcome. To improve the management of this complex patient population, we performed a comprehensive analysis of their anatomic and clinical features along with an evaluation of resource utilization data. The objectives were to describe anatomic and clinical features of patients with HS syndrome treated at a single center from 1992 to 2011 focusing on the impact of ventricular morphology (univentricular [UV] vs.

Rer1p maintains ciliary length and signaling by regulating γ-secretase activity and Foxj1a levels.

Cilia project from the surface of most vertebrate cells and are important for several physiological and developmental processes. Ciliary defects are linked to a variety of human diseases, named ciliopathies, underscoring the importance of understanding signaling pathways involved in cilia formation and maintenance. In this paper, we identified Rer1p as the first endoplasmic reticulum/cis-Golgi-localized membrane protein involved in ciliogenesis.

A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect.

Non-synonymous variants in pre-B cell leukemia homeobox (PBX) genes are associated with congenital heart defects.

Congenital cardiac malformations are one of the most common birth defects and most are believed to be multigenic/multifactorial in nature. Recently mice lacking Pre-B cell leukemia transcription homeobox (PBX) genes were created and found to have a range of ventricular outflow tract (OFT) malformations. Therefore, we screened 95 patients with congenital heart defects, including OFT malformations, for variants in genes encoding PBX proteins, as well as interacting proteins.

Exome analysis of a family with pleiotropic congenital heart disease.

Background: A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD.

Somatic mosaicism contributes to phenotypic variation in Timothy syndrome.

Timothy syndrome type 1 (TS-1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS-1 are the result of a missense mutation in exon 8A (p.G406R), an alternatively spliced variant of the L-type calcium channel gene (Ca(v)1.

Renin-angiotensin-aldosterone genotype influences ventricular remodeling in infants with single ventricle.

Background: We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle.

Methods And Results: Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles.

Patent foramen ovale in children with migraine headaches.

Objective: To determine the prevalence of patent foramen ovale (PFO) in children with migraine.

Study Design: Children aged 6.0 to 18.

Human balanced translocation and mouse gene inactivation implicate Basonuclin 2 in distal urethral development.

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was ∼400  kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein.

Extra-embryonic syndecan 2 regulates organ primordia migration and fibrillogenesis throughout the zebrafish embryo.

One of the first steps in zebrafish heart and gut organogenesis is the migration of bilateral primordia to the midline to form cardiac and gut tubes. The mechanisms that regulate this process are poorly understood. Here we show that the proteoglycan syndecan 2 (Sdc2) expressed in the extra-embryonic yolk syncytial layer (YSL) acts locally at the YSL-embryo interface to direct organ primordia migration, and is required for fibronectin and laminin matrix assembly throughout the embryo.