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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    ABSTRACT: Objective Array comparative genomic hybridization (aCGH) is a molecular cytogenetic technique that is able to detect the presence of copy number variants (CNVs) within the genome. The detection rate of imbalances of aCGH compared to the standard karyotype and FISH 22q11 in the setting of prenatally diagnosed cardiac malformations has been reported in several studies. The objective of our study was to perform a systematic literature review and meta-anlysis to document the additional diagnostic gain of aCGH in cases of congenital heart disease (CHD) diagnosed on prenatal ultrasound, in order to assist clinicians to determine whether aCGH analysis is warranted when ultrasonographic diagnosis of CHD is made, and to guide counseling in this setting.Methods All articles in the PubMed, Embase and Web of Science database from January 2007 to September 2014 describing CNVs in prenatal cases of CHD were included. Search terms were: array comparative genomic hybridization, copy number variants, fetal congenital heart defects. Articles regarding karyotyping or 22q11 deletion only were excluded.ResultsThirteen publications met the inclusion criteria for the analysis. Meta-analysis indicates an incremental yield of 7,0% (95% CI 5,3; 8,6) by aCGH, after exclusion of aneuploidy and 22q11 microdeletion. Subgroup results show 3,4%(95% CI 0,3; 6,6) incremental yield in isolated CHD and 9,3% (95% CI 6,6; 12) when extracardiac malformations are present. Overall incremental yield of 12% (95%CI 7,6; 16) was found including 22q11 deletion. There was an additional yield of 3,4% (95%CI 2,1; 4,6) of variants of unknown significance (VOUS).DiscussionIn this review, we provide an overview of published data and discuss benefits and limitations of aCGH. If karyotyping and FISH22q11 are normal, aCGH has an additional value, detecting pathogenic CNV in 7,0% of prenatally encountered CHD, with a 3,4% additional yield of VOUS.
    Ultrasound in Obstetrics and Gynecology 01/2015; 45(1). DOI:10.1002/uog.14695 · 3.14 Impact Factor
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    ABSTRACT: Congenital heart diseases (CHDs) are recognized as the most common type of birth malformations. Although recent advances in pre- and neonatal diagnosis as well as in surgical procedures have reduced the morbidity and mortality for many CHD, the etiology for CHD remains undefined. In non-syndromic and isolated (without a familial history or a Mendelian inheritance) forms of CHDs, a multifactorial pathogenesis with interplay between inherited and non-inherited causes is recognized. In this paper, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal cardiac development in non-syndromic and isolated CHD, including mutations in cardiac transcription factors, the role of somatic mutations and epigenetic alterations as well as the influence of gene-environment interactions. In the near future, the advent of high-throughput genomic technologies with the integration of system biology will expand our understanding of isolated, non-syndromic CHDs for their prevention, early diagnosis and therapy.
    Journal of Applied Statistics 10/2014; 15(5). DOI:10.2174/1389202915666140716175634 · 0.45 Impact Factor
  • 09/2014; 2(3):168-178. DOI:10.1007/s40142-014-0049-3


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Jun 2, 2014