title: A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia.
abstract: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
authors.affiliation: Department of Pediatrics (Cardiology), University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Cammon B
authors.initials: CB
authors.lastname: Arrington
authors.forename: Steven B
authors.initials: SB
authors.lastname: Bleyl
authors.forename: Nori
authors.initials: N
authors.lastname: Matsunami
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Tami I
authors.initials: TI
authors.lastname: Leppert
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Demarest
authors.forename: Karen
authors.initials: K
authors.lastname: Osborne
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Yoder
authors.forename: Janice L
authors.initials: JL
authors.lastname: Byrne
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.forename: Donald M
authors.initials: DM
authors.lastname: Null
authors.forename: Robert
authors.initials: R
authors.lastname: DiGeronimo
authors.forename: Michael
authors.initials: M
authors.lastname: Rollins
authors.forename: Roger
authors.initials: R
authors.lastname: Faix
authors.forename: Jessica
authors.initials: J
authors.lastname: Comstock
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Camp
authors.forename: Mark F
authors.initials: MF
authors.lastname: Leppert
authors.forename: H Joseph
authors.initials: HJ
authors.lastname: Yost
authors.forename: Luca
authors.initials: L
authors.lastname: Brunelli
mesh_terms: D000328:Adult; D051837:COUP Transcription Factor II / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002877:Chromosomes, Human; D015331:Cohort Studies; D004247:DNA / Q000097:blood / Q000235:genetics; D003964:Diaphragm / Q000002:abnormalities; D005192:Family Health; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006548:Hernia, Diaphragmatic / Q000097:blood / Q000235:genetics; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D051837:COUP Transcription Factor II; D004247:DNA; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C095569:NR2F2 protein, human