Copy number variations in individuals with conotruncal heart defects reveal some shared developmental pathways irrespective of 22q11.2 deletion status

Hongbo M. Xie, Deanne M. Taylor, Zhe Zhang, Donna M. McDonald-McGinn, Elaine H. Zackai, Dwight Stambolian, Hakon Hakonarson, Bernice E. Morrow, Beverly S. Emanuel, Elizabeth Goldmuntz

Research output: Contribution to journalArticle

Abstract

Over 50% of patients with 22q11.2 deletion syndrome (DS) have a conotruncal or related cardiac defect (CTRD). We hypothesized that similar genetic variants, developmental pathways and biological functions, contribute to disease risk for CTRD in patients without a 22q11.2 deletion (ND-CTRD) and with a 22q11.2 deletion (DS-CTRD). To test this hypothesis, we performed rare CNV (rCNV)-based analyses on 630 ND-CTRD cases and 602 DS-CTRD cases with comparable cardiac lesions separately and jointly. First, we detected a collection of heart development related pathways from Gene Ontology and Mammalian Phenotype Ontology analysis. We then constructed gene regulation networks using unique genes collected from the rCNVs found in the ND-CTRD and DS-CTRD cohorts. These gene networks were clustered and their predicted functions were examined. We further investigated expression patterns of those unique genes using publicly available mouse embryo microarray expression data from single-cell embryos to fully developed hearts. By these bioinformatics approaches, we identified a commonly shared gene expression pattern in both the ND-CTRD and DS-CTRD cohorts. Computational analysis of gene functions characterized with this expression pattern revealed a collection of significantly enriched terms related to cardiovascular development. By our combined analysis of rCNVs in the ND-CTRD and DS-CTRD cohorts, a group of statistically significant shared pathways, biological functions, and gene expression patterns were identified that can be tested in future studies for their biological relevance.

Original languageEnglish (US)
Pages (from-to)888-905
Number of pages18
JournalBirth Defects Research
Volume111
Issue number13
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • 22q11.2 deletion syndrome
  • conotruncal or related cardiac defect
  • functional analysis
  • gene interaction networks
  • mouse heart gene expression
  • pathway analysis
  • rare CNV

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis

Cite this

Xie, H. M., Taylor, D. M., Zhang, Z., McDonald-McGinn, D. M., Zackai, E. H., Stambolian, D., ... Goldmuntz, E. (2019). Copy number variations in individuals with conotruncal heart defects reveal some shared developmental pathways irrespective of 22q11.2 deletion status. Birth Defects Research, 111(13), 888-905. https://doi.org/10.1002/bdr2.1534