Rare Copy Number Variants in a Population Based Investigation of Hypoplastic Right Heart Syndrome

Details

• Alternative Title:
  Birth Defects Res
• Personal Author:
  Dimopoulos, Aggeliki ; Sicko, Robert J. ; Kay, Denise M. ; Rigler, Shannon L. ; Druschel, Charlotte M. ; Caggana, Michele ; Browne, Marilyn L. ; Fan, Ruzong ; Romitti, Paul A. ; Brody, Lawrence C. ; Mills, James L.
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• Description:
  Background ; Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdevelopment of the right heart structures commonly accompanied by an atrial septal defect. Familial HRHS reports suggest genetic factor involvement. We examined the role of copy number variants (CNVs) in HRHS. ; Methods ; We genotyped 32 HRHS cases identified from all New York State live births (1998–2005) using Illumina HumanOmni2.5 microarrays. CNVs were called with PennCNV and prioritized if they were ≥20Kb, contained ≥10 SNPs and had minimal overlap with CNVs from in-house controls, the Database of Genomic Variants, HapMap3 and CHOP database. ; Results ; We identified 28 CNVs in 17 cases; several encompassed genes important for right heart development. One case had a 2p16–2p23 duplication spanning LBH, a limb and heart development transcription factor. Lbh mis-expression results in right ventricular hypoplasia and pulmonary valve defects. This duplication also encompassed SOS1, a factor associated with pulmonary valve stenosis in Noonan syndrome. Sos1−/− mice display thin and poorly trabeculated ventricles. In another case, we identified a 1.5Mb deletion associated with Williams Beuren syndrome, a disorder that includes valvular malformations. A third case had a 24Kb deletion upstream of the TGFβ ligand ITGB8. Embryos genetically null for Itgb8, and its intracellular interactant Band 4.1B, display lethal cardiac phenotypes. ; Conclusions ; To our knowledge, this is the first study of CNVs in HRHS. We identified several rare CNVs that overlap genes related to right ventricular wall and valve development, suggesting that genetics plays a role in HRHS and providing clues for further investigation.
• Subjects:
  • Child
  • Child, Preschool
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Databases, Nucleic Acid
  • Female
  • Genotype
  • Heart Defects, Congenital
  • Heart Ventricles
  • Humans
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• Keywords:
  • hypoplastic right heart
  • hypoplastic right ventricle
  • copy number variants
  • SOS1
  • LBH
  • ITGB8
  • PRRX2
• Source:
  Birth Defects Res. 109(1):8-15
• Pubmed ID:
  28009100
• Pubmed Central ID:
  PMC5388571
• Document Type:
  Journal Article
• Funding:
  U01 DD001035/DD/NCBDD CDC HHSUnited States/ ; HHSN275201100001I/HD/NICHD NIH HHSUnited States/ ; HHSN275201100001C/HD/NICHD NIH HHSUnited States/ ; N01DK73431/HD/NICHD NIH HHSUnited States/ ; Z01 HD008792-01/ImNIH/Intramural NIH HHSUnited States/ ; HHSN275201100001G/HD/NICHD NIH HHSUnited States/
• Volume:
  109
• Issue:
  1
• Download URL:
  https://stacks.cdc.gov/view/cdc/82845/cdc_82845_DS1.pdf
• File Type:
  [PDF - 348.03 KB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:483eb86d04cf077ba9f5e8d13675ade0bc062828de38df38a452316446b9cd69746d80f32b88346a42f2b96be506c13caf0f75f793d2c412b5229b2d1fcdb904