Your browser doesn't support javascript.
loading
Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.
Glessner, Joseph T; Bick, Alexander G; Ito, Kaoru; Homsy, Jason; Rodriguez-Murillo, Laura; Fromer, Menachem; Mazaika, Erica; Vardarajan, Badri; Italia, Michael; Leipzig, Jeremy; DePalma, Steven R; Golhar, Ryan; Sanders, Stephan J; Yamrom, Boris; Ronemus, Michael; Iossifov, Ivan; Willsey, A Jeremy; State, Matthew W; Kaltman, Jonathan R; White, Peter S; Shen, Yufeng; Warburton, Dorothy; Brueckner, Martina; Seidman, Christine; Goldmuntz, Elizabeth; Gelb, Bruce D; Lifton, Richard; Seidman, Jonathan; Hakonarson, Hakon; Chung, Wendy K.
Afiliación
  • Glessner JT; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Bick AG; Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Ito K; Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Homsy J; Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Rodriguez-Murillo L; Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Fromer M; Mindich Child Health and Development Institute, Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Mazaika E; Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Vardarajan B; Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Italia M; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Leipzig J; Psychiatric Genomics in the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • DePalma SR; Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Golhar R; Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Sanders SJ; Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Yamrom B; Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Ronemus M; Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Iossifov I; The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Willsey AJ; Genetics, Yale University, New Haven, CT 06520, USA.
  • State MW; Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kaltman JR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • White PS; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Shen Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • Warburton D; Genetics, Yale University, New Haven, CT 06520, USA.
  • Brueckner M; Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Seidman C; Genetics, Yale University, New Haven, CT 06520, USA.
  • Goldmuntz E; Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Gelb BD; Cardiovascular Sciences, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, MD 20892, USA.
  • Lifton R; Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Seidman J; Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
  • Hakonarson H; Genetics and Development (in Medicine), Columbia University Medical Center, New York, NY 10032, USA.
  • Chung WK; Pediatrics, Yale University, New Haven, CT 06520, USA.
Circ Res ; 115(10): 884-896, 2014 Oct 24.
Article en En | MEDLINE | ID: mdl-25205790
RATIONALE: 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. METHODS AND 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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Polimorfismo de Nucleótido Simple / Variaciones en el Número de Copia de ADN / Exoma / Frecuencia de los Genes / Cardiopatías Congénitas Tipo de estudio: Diagnostic_studies / Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Circ Res Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Polimorfismo de Nucleótido Simple / Variaciones en el Número de Copia de ADN / Exoma / Frecuencia de los Genes / Cardiopatías Congénitas Tipo de estudio: Diagnostic_studies / Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Circ Res Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos