title: Effect of copy number variants on outcomes for infants with single ventricle heart defects.
abstract: BACKGROUND
  Human genomes harbor copy number variants (CNVs), which are regions of DNA gains or losses. Although pathogenic CNVs are associated with congenital heart disease (CHD), their effect on clinical outcomes is unknown. This study sought to determine whether pathogenic CNVs among infants with single ventricle physiology were associated with inferior neurocognitive and somatic growth outcomes.
  
  
  RESULTS
  Genomic DNAs from 223 subjects of 2 National Heart, Lung, and Blood Institute-sponsored randomized clinical trials in infants with single ventricle CHD and 270 controls from The Cancer Genome Atlas project were analyzed for rare CNVs>300 kb using array comparative genomic hybridization. Neurocognitive and growth outcomes at 14 months from the CHD trials were compared among subjects with and without pathogenic CNVs. Putatively pathogenic CNVs, comprising 25 duplications and 6 deletions, had a prevalence of 13.9%, significantly greater than the 4.4% rate of such CNVs among controls. CNVs associated with genomic disorders were found in 13 cases but not in controls. Several CNVs likely to be causative of single ventricle CHD were observed, including aberrations altering the dosage of GATA4, MYH11, and GJA5. Subjects with pathogenic CNVs had worse linear growth, and those with CNVs associated with known genomic disorders had the poorest neurocognitive and growth outcomes. A minority of children with pathogenic CNVs were noted to be dysmorphic on clinical genetics examination.
  
  
  CONCLUSIONS
  Pathogenic CNVs seem to contribute to the cause of single ventricle forms of CHD in ≥10% of cases and are clinically subtle but adversely affect outcomes in children harboring them.
authors.affiliation: Mindich Child Health and Development Institute.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Carey
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Edwards
authors.forename: Tracy
authors.initials: T
authors.lastname: Brandt
authors.forename: Hui
authors.initials: H
authors.lastname: Mei
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.forename: Daphne T
authors.initials: DT
authors.lastname: Hsu
authors.forename: Jane W
authors.initials: JW
authors.lastname: Newburger
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ohye
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russell
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Michael K
authors.initials: MK
authors.lastname: Parides
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D017630:Connexins / Q000235:genetics; D056915:DNA Copy Number Variations; D050991:GATA4 Transcription Factor / Q000235:genetics; D015894:Genome, Human; D005838:Genotype; D006330:Heart Defects, Congenital / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D018995:Myosin Heavy Chains / Q000235:genetics; D015995:Prevalence; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D050991:GATA4 Transcription Factor; D018995:Myosin Heavy Chains; D000097003:Gap Junction alpha-5 Protein; C484170:GATA4 protein, human; C509903:MYH11 protein, human
keywords: DNA copy number variantiations; congenital cardiac defect; hypoplastic left heart syndrome; outcome
references.citation: Circulation. 2007 Jun 12;115(23):3015-38
references.pmid: 17519398
references.citation: Eur Heart J. 2007 Nov;28(22):2778-84
references.pmid: 17384091
references.citation: Am J Hum Genet. 2009 Feb;84(2):148-61
references.pmid: 19166990
references.citation: Nat Genet. 2009 Aug;41(8):931-5
references.pmid: 19597493
references.citation: Eur J Hum Genet. 2011 Mar;19(3):280-6
references.pmid: 21150890
references.citation: Science. 2007 Apr 20;316(5823):445-9
references.pmid: 17363630
references.citation: Am J Med Genet A. 2007 Jul 1;143A(13):1462-71
references.pmid: 17568417
references.citation: Physiol Genomics. 2012 May 1;44(9):518-41
references.pmid: 22318994
references.citation: Mol Psychiatry. 2011 Jan;16(1):17-25
references.pmid: 19786961
references.citation: Am J Med Genet A. 2006 Nov 15;140(22):2426-32
references.pmid: 17041934
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: Nat Genet. 2006 Mar;38(3):343-9
references.pmid: 16444274
references.citation: J Neurodev Disord. 2010 Mar;2(1):26-38
references.pmid: 21731881
references.citation: Am J Med Genet A. 2010 Jun;152A(6):1561-6
references.pmid: 20503336
references.citation: Circ Cardiovasc Genet. 2011 Dec;4(6):620-5
references.pmid: 21933911
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2012 Apr;159B(3):263-73
references.pmid: 22344817
references.citation: Hum Mutat. 2007 Jul;28(7):674-82
references.pmid: 17480035
references.citation: Am J Hum Genet. 1999 Apr;64(4):1119-26
references.pmid: 10090897
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17076-81
references.pmid: 21969575
references.citation: Am J Hum Genet. 2008 Jan;82(1):214-21
references.pmid: 18179902
references.citation: Nat Genet. 2010 May;42(5):400-5
references.pmid: 20364138
references.citation: Nature. 2003 Jul 24;424(6947):443-7
references.pmid: 12845333
references.citation: PLoS Genet. 2011 Jun;7(6):e1002118
references.pmid: 21698135
references.citation: Zhongguo Dang Dai Er Ke Za Zhi. 2009 Nov;11(11):892-6
references.pmid: 20113655
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Am J Hum Genet. 2010 May 14;86(5):749-64
references.pmid: 20466091
references.citation: J Med Genet. 2008 Nov;45(11):704-9
references.pmid: 18713793
references.citation: Pediatr Cardiol. 2012 Jun;33(5):757-63
references.pmid: 22349727
references.citation: Int J Dev Biol. 2003 Jun;47(5):345-54
references.pmid: 12895029
references.citation: N Engl J Med. 2012 Oct 4;367(14):1321-31
references.pmid: 22970919
references.citation: Genet Med. 2010 Nov;12(11):694-702
references.pmid: 20808228
references.citation: Hum Mol Genet. 2009 Apr 15;18(8):1377-83
references.pmid: 19193630
references.citation: Pediatr Res. 2008 Oct;64(4):358-63
references.pmid: 18535492
references.citation: Am J Hum Genet. 2012 Sep 7;91(3):489-501
references.pmid: 22939634
references.citation: Hum Mol Genet. 2012 Apr 1;21(7):1513-20
references.pmid: 22199024
references.citation: Circulation. 2012 May 1;125(17):2081-91
references.pmid: 22456475
references.citation: Mol Cytogenet. 2010 Feb 18;3:3
references.pmid: 20167067
references.citation: Prenat Diagn. 2012 Jun;32(6):611
references.pmid: 22622835
references.citation: Nat Genet. 2011 Aug 14;43(9):838-46
references.pmid: 21841781
references.citation: N Engl J Med. 2008 Feb 14;358(7):667-75
references.pmid: 18184952
references.citation: Am J Med Genet A. 2009 Aug;149A(8):1661-77
references.pmid: 19606479
references.citation: Circulation. 2010 Jul 27;122(4):333-40
references.pmid: 20625111
references.citation: PLoS Genet. 2012 Sep;8(9):e1002903
references.pmid: 22969434
references.citation: Genet Med. 2011 Sep;13(9):777-84
references.pmid: 21844811
references.citation: J Pediatr. 2010 May;156(5):810-7, 817.e1-817.e4
references.pmid: 20138633
references.citation: Curr Drug Targets. 2011 May;12(5):671-82
references.pmid: 21039331
references.citation: N Engl J Med. 2010 May 27;362(21):1980-92
references.pmid: 20505177
references.citation: Prog Neurobiol. 2012 Oct;99(1):81-91
references.pmid: 22813947
references.citation: Eur J Hum Genet. 2012 Jul;20(7):754-61
references.pmid: 22317977
references.citation: Nature. 2006 Nov 23;444(7118):444-54
references.pmid: 17122850