Article

Submicroscopic Chromosomal Copy Number Variations Identified in Children With Hypoplastic Left Heart Syndrome

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Pediatric Cardiology (Impact Factor: 1.55). 02/2012; 33(5):757-63. DOI: 10.1007/s00246-012-0208-9
Source: PubMed

ABSTRACT Hypoplastic left heart syndrome (HLHS), one of the most severe types of congenital heart disease (CHD), results in significant morbidity and mortality despite surgical palliation. The etiology of HLHS is unknown, but evidence supports genetic contributors. The authors hypothesized that submicroscopic chromosomal abnormalities exist in individuals with HLHS and are more frequent in those with additional birth defects. This study sought to determine the incidence and genomic location of submicroscopic chromosomal abnormalities in HLHS and potentially to identify novel genetic loci that may contribute to the disease. For this study, 43 children with HLHS were recruited and screened together with a control population of 16 subjects using array comparative genomic hybridization, also called chromosomal microarray, for chromosomal copy number variations (CNVs). A statistically greater number of CNVs were found in the HLHS group than in the control group (p < 0.03). The CNVs were predominantly small autosomal deletions and duplications (≤ 60,000 bp). The frequency of unique CNVs, those not previously reported in public databases, did not differ statistically between the HLHS subjects and the control subjects. No difference in the frequency of CNVs was noted between the patients with HLHS and additional anomalies and those with isolated HLHS. The identified CNVs did not harbor potential candidate genes for HLHS, but one microdeletion was located on chromosome 14q23, a genetic locus linked to left-sided CHD. The study data demonstrate that CNVs, specifically those relatively small in size, are more common in subjects with HLHS, but the frequency of large potentially disease-causing CNVs (>480,000 bp) did not differ between the HLHS and control populations.

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    • "- ulation and / or the variety of analytical approaches taken . Presumably in the future the evaluation of significantly larger cohorts will converge around a subset of disease - related genes and functional pathways . In the meantime , the clinical utility of array - based CNV analysis in the spo - radic , nonsyndromic patient remains uncertain ( Payne et al . , 2012 ; Warburton et al . , 2014 ) . Our report , as with others , is primarily limited by the study size , given the apparent genetic heterogeneity of LSCD . However , in the current study , cases were consis - tently and thoroughly phenotyped in a single center , con - trols were derived from a healthy pediatric population , cases and contr"
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    ABSTRACT: Background: We sought to characterize the landscape of structural variation associated with the subset of congenital cardiac defects characterized by left-sided obstruction. Methods: Cases with left-sided cardiac defects (LSCD) and pediatric controls were uniformly genotyped and assessed for copy number variant (CNV) calls. Significance testing was performed to ascertain differences in overall CNV incidence, and for CNV enrichment of specific genes and gene functions in LSCD cases relative to controls. Results: A total of 257 cases of European descent and 962 ethnically matched, disease-free pediatric controls were included. Although there was no difference in CNV rate between cases and controls, a significant enrichment in rare LSCD CNVs was detected overall (p = 7.30 × 10−3, case/control ratio = 1.26) and when restricted either to deletions (p = 7.58 × 10−3, case/control ratio = 1.20) or duplications (3.02 × 10−3, case/control ratio = 1.43). Neither gene-based, functional nor knowledge-based analyses identified genes, loci or pathways that were significantly enriched in cases as compared to controls when appropriate corrections for multiple tests were applied. However, several genes of interest were identified by virtue of their association with cardiac development, known human conditions, or reported disruption by CNVs in other patient cohorts. Conclusion: This study examines the largest cohort to date with LSCD for structural variation. These data suggest that CNVs play a role in disease risk and identify numerous genes disrupted by CNVs of potential disease relevance. These findings further highlight the genetic heterogeneity and complexity of these disorders. Birth Defects Research (Part A), 2014. © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 12/2014; 100(12). DOI:10.1002/bdra.23279 · 2.21 Impact Factor
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    • "Recent studies have demonstrated the utility of microarraybased approaches to uncover subtle chromosome abnormalities in children with multiple birth defects [Richards and Garg, 2010; Richards et al., 2008]. Chromosomal microarray or array comparative genome hybridization is a relatively new technology that has gained clinical utility to investigate genetic etiologies for complex forms of CHD, especially when it is associated with other birth defects [Payne et al., 2012; Richards and Garg, 2010]. Use of this technology has been important for identifying chromosomal abnormalities in children with CHD, and even for discovering new genetic syndromes associated with chromosomal abnormalities. "
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    ABSTRACT: The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ∼0.3Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first 4 exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine if FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD. This article is protected by copyright. All rights reserved.
    Human Mutation 09/2013; 34(9). DOI:10.1002/humu.22366 · 5.05 Impact Factor
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    ABSTRACT: Background With an increasing incidence of congenital heart defects (CHDs) in recent years, genotype-phenotype correlation and array-based methods have contributed to the genome-wide analysis and understanding of genetic variations in the CHD population. Here, we report a copy number deletion of chromosomal 14q23.1 in a female fetus with complex congenital heart defects. This is the first description of DAAM1 gene deletion associated with congenital heart anomalies. Case Presentation Compared with the control population, one CHD fetus showed a unique copy number deletion of 14q23.1, a region that harbored DAAM1 and KIAA0666 genes. Conclusions Results suggest that the copy number deletion on chromosome 14q23.1 may be critical for cardiogenesis. However, the exact relationship and mechanism of how DAAM1 and KIAA0666 deletion contributes to the onset of CHD is yet to be determined.
    BMC Medical Genetics 08/2012; 13(1):63. DOI:10.1186/1471-2350-13-63 · 2.45 Impact Factor
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