Pediatr Res

. 2023 Sep 12.

 doi: 10.1038/s41390-023-02811-y. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/37700164/

Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis

Jun Yasuhara ^1 2, Sathiya N Manivannan ^1 2, Uddalak Majumdar ^1 2, David M Gordon ³, Patrick J Lawrence ³, Mona Aljuhani ^1 2, Katherine Myers ^1 2, Corey Stiver ^2 4, Amee M Bigelow ⁴, Mark Galantowicz ², Hiroyuki Yamagishi ⁵, Kim L McBride ^1 2 4 6, Peter White ^3 4, Vidu Garg ^7 8 9 10

Affiliations expand

• PMID: 37700164
• DOI: 10.1038/s41390-023-02811-y

Abstract

Background: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood.

Methods: Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay.

Results: A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity.

Conclusions: We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities.

Impact: Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.