Dataset Information

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.

SUBMITTER: Yu L

PROVIDER: S-EPMC3570587 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

Yu Lan L Wynn Julia J Cheung Yee Him YH Shen Yufeng Y Mychaliska George B GB Crombleholme Timothy M TM Azarow Kenneth S KS Lim Foong Yen FY Chung Dai H DH Potoka Douglas D Warner Brad W BW Bucher Brian B Stolar Charles C Aspelund Gudrun G Arkovitz Marc S MS Chung Wendy K WK

Human genetics 20121109 3

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) ...[more]

PMID: 23138528

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Project description:Congenital diaphragmatic hernia (CDH) is a common and severe structural malformation in which the high rate of morbidity and mortality is caused by lung hypoplasia and pulmonary hypertension. Genetic variants have been identified in 30% of CDH patients and are associated with increased morbidity and mortality but it is unclear how these variants impact lung and pulmonary vascular defect severity. Deletions of 8p23.1 account for 3-5% of cases and encompass GATA4, a transcription factor that directs gene expression throughout the developing embryo. CDH patients with GATA4 haploinsufficiency have high mortality and severe lung hypoplasia and pulmonary hypertension. Given this information, our aim was to characterize the role of GATA4 during lung and pulmonary vascular development. We generated mice with lung-specific deletion of Gata4 and found that GATA4 is not required during lung or pulmonary vascular development. However, mice with diaphragm-specific inactivation of Gata4 (Gata4 D-CKO) die after birth with abnormal diaphragm formation and lung hypoplasia thus we focused on the latest stage of embryonic development. We obtained whole lung RNA at embryonic day 18 (E18) at the latest stage prior to delivery due to early postnatal death of Gata4 D-CKO mice. We performed bulk RNA sequencing on control embryos (termed Gata4 D-control, Prx1Cre;Gata4F/+) and embryos with diaphragm-specific inactivation of Gata4 (termed Gata4 D-CKO, Prx1Cre;Gata4F/D). In this bulk RNA sequencing dataset are expression data from Gata4 D-control and D-CKO whole lungs at E18 implicating abnormal expression of genes involved in cell cycling and motor protein pathways. Mechanical compression of the embryonic lungs was also associated with increased phosphorylation of mechanosensory protein YAP1 resulting in decreased cell cycling. Our data suggest that the lung and pulmonary vascular phenotype of patients with CDH and GATA4 haploinsufficiency is due to mechanical compression.

Dataset Information

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

Publications

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

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