title: Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.
abstract: Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two "unaffected" missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.
authors.affiliation: Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY 10032, USA. ly2255@columbia.edu
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.forename: Julia
authors.initials: J
authors.lastname: Wynn
authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Shen
authors.forename: George B
authors.initials: GB
authors.lastname: Mychaliska
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Azarow
authors.forename: Foong Yen
authors.initials: FY
authors.lastname: Lim
authors.forename: Dai H
authors.initials: DH
authors.lastname: Chung
authors.forename: Douglas
authors.initials: D
authors.lastname: Potoka
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
authors.forename: Brian
authors.initials: B
authors.lastname: Bucher
authors.forename: Charles
authors.initials: C
authors.lastname: Stolar
authors.forename: Gudrun
authors.initials: G
authors.lastname: Aspelund
authors.forename: Marc S
authors.initials: MS
authors.lastname: Arkovitz
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006548:Hernia, Diaphragmatic / Q000235:genetics; D065630:Hernias, Diaphragmatic, Congenital; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human