Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks

Publication: Research - peer-reviewJournal article – Annual report year: 2012

  • Author: Longoni, Mauro

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Hansen, Kasper Lage

    Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark

  • Author: Russell, Meaghan K.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Loscertales, Maria

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Abdul‐Rahman, Omar A.

    Department of Pediatrics, University of Mississippi Medical Center, United States

  • Author: Baynam, Gareth

    Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia

  • Author: Bleyl, Steven B.

    Department of Pediatrics, University of Utah School of Medicine, United States

  • Author: Brady, Paul D.

    Laboratory for CytogenCentre for Human Genetics, University Hospital Leuven, Belgium

  • Author: Breckpot, Jeroen

    Laboratory for CCentre for Human Genetics, University Hospital Leuven, Belgium

  • Author: Chen, Chih P.

    Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taiwan, Province of China

  • Author: Devriendt, Koenraad

    Centre for Human Genetics, University Hospital Leuven, Belgium

  • Author: Gillessen‐Kaesbach, Gabriele

    Institut für Humangenetik, Universität zu Lübeck, Germany

  • Author: Grix, Arthur W.

    Genetics, Kaiser Permanente, United States

  • Author: Rope, Alan F.

    Department of Pediatrics, University of Utah School of Medicine, United States

  • Author: Shimokawa, Osamu

    Department of Molecular Genetic Testing, Mitsubishi Chemical Medience Corporation, Japan

  • Author: Strauss, Bernarda

    Mercy Children's Hospital, Kansas City, United States

  • Author: Wieczorek, Dagmar

    Institut für Humangenetik, Universitätsklinikum Essen, Germany

  • Author: Zackai, Elaine H.

    Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, United States

  • Author: Coletti, Caroline M.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Maalouf, Faouzi I.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Noonan, Kristin M.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Park, Ji H.

    Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, United States

  • Author: Tracy, Adam A.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts

  • Author: Lee, Charles

    Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

  • Author: Donahoe, Patricia K.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

  • Author: Pober, Barbara R.

    Pediatric Surgical Research Laboratories, Massachusetts General Hospital, United States

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Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high‐resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub‐band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein–protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5–12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks. © 2012 Wiley Periodicals, Inc.
Original languageEnglish
JournalAmerican Journal of Medical Genetics. Part A
Publication date2012
Volume158A
Issue12
Pages3148-3158
ISSN1552-4825
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 5
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