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Rare copy number variants in patients with congenital conotruncal heart defects.

ABSTRACT: BACKGROUND:Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome. METHODS:Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls. RESULTS:Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development. CONCLUSION:Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Xie HM

PROVIDER: S-EPMC5407323 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Rare copy number variants in patients with congenital conotruncal heart defects.

Xie Hongbo M HM Werner Petra P Stambolian Dwight D Bailey-Wilson Joan E JE Hakonarson Hakon H White Peter S PS Taylor Deanne M DM Goldmuntz Elizabeth E

Birth defects research 20170213 4

<h4>Background</h4>Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome.<h4>Methods</h4>Cases and control samples were divided into two cohorts and genotyped to assess each ...[more]

PMID: 28398664

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Project description:BackgroundHeterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx.MethodsWe collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models.ResultsNineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning.ConclusionsOur findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.

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Rare copy number variants in patients with congenital conotruncal heart defects.

Publications

Rare copy number variants in patients with congenital conotruncal heart defects.

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