title: Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.
abstract: 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.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. mlongoni@partners.org
authors.forename: Mauro
authors.initials: M
authors.lastname: Longoni
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.forename: Meaghan K
authors.initials: MK
authors.lastname: Russell
authors.forename: Maria
authors.initials: M
authors.lastname: Loscertales
authors.forename: Omar A
authors.initials: OA
authors.lastname: Abdul-Rahman
authors.forename: Gareth
authors.initials: G
authors.lastname: Baynam
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brady
authors.forename: Jeroen
authors.initials: J
authors.lastname: Breckpot
authors.forename: Chih P
authors.initials: CP
authors.lastname: Chen
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Grix
authors.forename: Alan F
authors.initials: AF
authors.lastname: Rope
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimokawa
authors.forename: Bernarda
authors.initials: B
authors.lastname: Strauss
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Coletti
authors.forename: Faouzi I
authors.initials: FI
authors.lastname: Maalouf
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Noonan
authors.forename: Ji H
authors.initials: JH
authors.lastname: Park
authors.forename: Adam A
authors.initials: AA
authors.lastname: Tracy
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Pober
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000097:blood / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D006330:Heart Defects, Congenital / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006548:Hernia, Diaphragmatic / Q000097:blood / Q000235:genetics / Q000378:metabolism; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011247:Pregnancy; D060066:Protein Interaction Maps; D055760:SOXF Transcription Factors / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C484456:SOX7 protein, human; D055760:SOXF Transcription Factors; D004247:DNA; D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C473642:NEIL2 protein, human