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  • Basic Science Article
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Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis

Pediatric Research volume 95, pages 146–155 (2024)Cite this article

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.

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Fig. 1: Novel missense GATA6 variant segregates with congenital heart disease and additional extracardiac disease in family.
Fig. 2: In vitro analysis of GATA6 p.Cys468Tyr variant.
Fig. 3: GATA6 variants associated with intestinal abnormalities.

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Data availability

Data presented in current publication have been deposited in and are available in dbGaP database under dbGaP accession phs002010.v1.p1. Some restrictions apply for dbGaP, as data is available to researchers who meet access criteria. Data access is through the dbGaP website and researchers apply for data access. Supplied accession number should be used to search the dataset on the website: https://www.ncbi.nlm.nih.gov/gap/.

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Acknowledgements

We thank the family members for study participation, Gloria Zender in Cell Line Core and Samantha Fichtner and Jade Hayden in Heart Center Clinical Research Core.

Funding

This work was supported in part by funding from National Institutes of Health (R01 HL109758) to V.G., K.L.M, and P.W.

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Authors and Affiliations

  1. Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA

    Jun Yasuhara, Sathiya N. Manivannan, Uddalak Majumdar, Mona Aljuhani, Katherine Myers, Kim L. McBride & Vidu Garg

  2. The Heart Center, Nationwide Children’s Hospital, Columbus, OH, USA

    Jun Yasuhara, Sathiya N. Manivannan, Uddalak Majumdar, Mona Aljuhani, Katherine Myers, Corey Stiver, Mark Galantowicz, Kim L. McBride & Vidu Garg

  3. Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

    David M. Gordon, Patrick J. Lawrence & Peter White

  4. Department of Pediatrics, The Ohio State University, Columbus, OH, USA

    Corey Stiver, Amee M. Bigelow, Kim L. McBride, Peter White & Vidu Garg

  5. Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

    Hiroyuki Yamagishi

  6. Division of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

    Kim L. McBride

  7. Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA

    Vidu Garg

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  1. Jun Yasuhara
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Contributions

J.Y. and V.G. conceived and designed the study. K.M, C.S., K.L.M, and V.G. enrolled patients. J.Y., M.A., K.M., and C.S. collected clinical data. J.Y., S.N.M., and U.M. performed and acquired experimental data. J.Y., S.N.M., D.M.G., P.J.L, and P.W. performed bioinformatics analyses. J.Y., S.N.M., U.M., D.M.G., P.J.L, K.L.M., P.W., and V.G. analyzed and interpreted the data. J.Y. and V.G. drafted the manuscript. C.S., A.M.B., M.G., H.Y., K.L.M., P.W., and V.G. critically reviewed the manuscript. All authors read and approved the final version of the manuscript for publication.

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Correspondence to Vidu Garg.

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Yasuhara, J., Manivannan, S.N., Majumdar, U. et al. Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis. Pediatr Res 95, 146–155 (2024). https://doi.org/10.1038/s41390-023-02811-y

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