title: Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.
abstract: BACKGROUND
  Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.
  
  
  OBJECTIVE
  To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.
  
  
  RESULTS
  We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.
  
  
  CONCLUSIONS
  We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
authors.affiliation: The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Homsy
authors.affiliation: Mindich Child Health and Development Institute, Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodriguez-Murillo
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Psychiatric Genomics in the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Mazaika
authors.affiliation: Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Italia
authors.affiliation: Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Leipzig
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.affiliation: The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Golhar
authors.affiliation: Genetics, Yale University, New Haven, CT 06520, USA.|Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Yamrom
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ronemus
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Iossifov
authors.affiliation: Genetics, Yale University, New Haven, CT 06520, USA.|Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: A Jeremy
authors.initials: AJ
authors.lastname: Willsey
authors.affiliation: Genetics, Yale University, New Haven, CT 06520, USA.|Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.affiliation: Cardiovascular Sciences, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Kaltman
authors.affiliation: Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: White
authors.affiliation: Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Genetics and Development (in Medicine), Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Pediatrics, Yale University, New Haven, CT 06520, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckner
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Seidman
authors.affiliation: Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.affiliation: Mindich Child Health and Development Institute, Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: Genetics, Yale University, New Haven, CT 06520, USA.|Medicine, Yale University, New Haven, CT 06520, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lifton
authors.affiliation: Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Seidman
authors.affiliation: The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
keywords: DNA copy number variations; genomics; microarray analysis; polymorphism, single nucleotide