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

Autor:	Yasuhara J; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Manivannan SN; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Majumdar U; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Gordon DM; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Lawrence PJ; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Aljuhani M; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Myers K; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Stiver C; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Bigelow AM; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Galantowicz M; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA., Yamagishi H; Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., McBride KL; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., White P; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Garg V; Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA. vidu.garg@nationwidechildrens.org.; The Heart Center, Nationwide Children's Hospital, Columbus, OH, USA. vidu.garg@nationwidechildrens.org.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA. vidu.garg@nationwidechildrens.org.; Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA. vidu.garg@nationwidechildrens.org.
Jazyk:	angličtina
Zdroj:	Pediatric research [Pediatr Res] 2024 Jan; Vol. 95 (1), pp. 146-155. Date of Electronic Publication: 2023 Sep 12.
DOI:	10.1038/s41390-023-02811-y
Abstrakt:	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.)
Databáze:	MEDLINE
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