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Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing
Jun Yasuhara1,2, Sathiya N Manivannan1,2, Uddalak Majumdar1,2
1Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
Insights
A novel GATA6 gene variant causes congenital heart disease, diabetes, and necrotizing enterocolitis. This discovery expands the known GATA6 gene mutation spectrum to include intestinal abnormalities.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Medical Genetics
Background:
- Pathogenic GATA6 variants are linked to congenital heart disease (CHD) and various extracardiac issues.
- A complete understanding of GATA6 genotype-phenotype correlations in humans is still developing.
Purpose of the Study:
- To investigate a family with multiple members affected by CHD.
- To identify the genetic basis of CHD and associated abnormalities in the studied family.
- To characterize the functional impact of a novel GATA6 variant.
Main Methods:
- Whole exome sequencing was utilized to analyze affected family members with CHD.
- In vitro functional studies, including immunofluorescence, western blot, and dual-luciferase reporter assays, were performed.
- The identified GATA6 variant's effect on protein localization and transcriptional activity was assessed.
Main Results:
- A novel heterozygous GATA6 missense variant (p.Cys468Tyr) was identified and segregated with CHD in the family.
- Affected individuals exhibited persistent truncus arteriosus, diabetes mellitus, and necrotizing enterocolitis with intestinal perforation.
- Functional assays revealed abnormal nuclear localization, protein aggregation, and reduced transcriptional activity of the mutant GATA6 protein.
Conclusions:
- A novel familial GATA6 variant (p.Cys468Tyr) is associated with CHD, diabetes mellitus, and necrotizing enterocolitis.
- This study expands the phenotypic spectrum of pathogenic GATA6 variation to include intestinal abnormalities.
- Neonatal intestinal perforation is identified as a novel extracardiac phenotype linked to GATA6 mutations.
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.
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