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.

Fig. 1

a Pedigree of the proband (arrow) with CDH. Squares indicate male subjects, and circles female subjects; slashes indicate deceased subjects; filled indicate affected subjects with CDH, filled with light gray indicate anatomical Bochdalek hernias who were clinically asymptomatic, unfilled clinically asymptomatic subjects. Genotypes of GATA4 c.C754T for all the available individuals are indicated. b Sequence chromatograms of GATA4 in proband, sibling, father and mother indicate the paternally inherited c. C754T (red arrow) in exon 3 resulting in an Arginine to Tryptophan amino acid substitution at amino acid 252. The sequence is the complementary strand.

Fig. 2

The 7 exons of GATA4 (Top). Filled squares with orange are coding exons of GATA4. Each * symbol represents a mutation in the coding exons from human genome mutation database. The c.C754T and c.G848A mutations are indicated in red, missense mutation c. G755C resulting in the Arginine to Proline at amino acid 252 is indicated in green; The protein of GATA4 (Middle). Two highly-conserved GATA-type zinc finger domains indicated as light blue. R252W indicated in red square. Amino acids alignment of a portion of GATA4 protein from different vertebrate species (Bottom). The Arginine at residue 252 is highlighted.

Fig. 3

MRI of chest and abdomen in GATA4 R252W carriers III.4 and II.3. a–b III.4 (father) has a small left Bochdalek hernia indicated by white arrow. c–d II.3 (grandfather) has a small left Bochdalek hernia indicated by white arrow and arrowhead.