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 (MRI) 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.

GATA4 variant identified by whole‐exome sequencing in a Japanese family with atrial septal defect: Implications for male sex development

“…This would primarily be consistent with the GATA4 variant in this family, because previous studies have shown that GATA4 variants, though they are occasionally accompanied by extra‐cardiac features such as 46,XY DSD6, 7 and congenital diaphragmatic hernia,14 usually lead to isolated CHDs (primarily ASD2). However, lack of extra‐cardiac features is not a common finding in CHDs in general.…”

Whole exome sequencing identifies de novo mutations inGATA6associated with congenital diaphragmatic hernia

“…Mutations in GATA4 , a paralogue of GATA6 , have recently been identified in only one of a cohort of 96 patients with CDH,5 so we reasoned that a larger cohort might be needed to find additional patients with GATA6 mutations. We took advantage of a recently described high throughput targeted sequencing approach,8 using MIPs to screen a cohort of 357 patients with CDH (clinical information in online supplementary table S4), 83 of whom overlapped with those Sanger sequenced.…”

“…This is likely due to the historically high mortality in CDH, resulting in very few multiplex families amenable to traditional linkage analysis. De novo rare variants have been identified as a cause of sporadic diseases with decreased reproductive fitness,4 and a pathogenic de novo variant in GATA4 was recently identified as a cause of CDH 5. Allen et al identified a de novo c.1516+4A>G mutation in GATA6 in a patient with pancreatic agenesis and CDH 6.…”

PBX transcription factors drive pulmonary vascular adaptation to birth

“…Recent genomic sequence analysis of patients with CDH, correlated with gene expression studies in the developing mouse diaphragm, has identified a growing list of candidate genes implicated in the pathogenesis of CDH (14,16,(20)(21)(22)(23). Among them are Pbx genes that encode homeodomain-containing transcription factors best known to act as Hox cofactors (24,25).…”