Whole-Exome Sequencing Identifies Novel GATA5/6 Variants in Right-Sided Congenital Heart Defects.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

GATA6 Transcription Factor*/genetics ; Exome Sequencing*/methods ; Heart Defects, Congenital*/genetics ; Heart Defects, Congenital*/diagnostic imaging ; GATA5 Transcription Factor*/genetics; Humans ; Female ; Male ; Polymorphism, Single Nucleotide ; Pedigree ; Infant, Newborn

One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important roles in embryonic development and their inactivation may result in congenital heart defects (CHDs). In this study, we performed genotypic-phenotypic analyses in two families affected by right-sided CHD diagnosed by echocardiography imaging. Proband A presented with pulmonary valve stenosis, and proband B presented with complex CHD involving the right heart structures. For variant detection, we employed whole-genome single-nucleotide polymorphism (SNP) microarray and family-based whole-exome sequencing (WES) studies. Proband A is a full-term infant who was admitted to the neonatal intensive care unit (NICU) at five days of life for pulmonary valve stenosis (PVS). Genomic studies revealed a normal SNP microarray; however, quad WES analysis identified a novel heterozygous [Chr20:g.61041597C>G (p.Arg237Pro)] variant in the GATA5 gene. Further analysis confirmed that the novel variant was inherited from the mother but was absent in the father and the maternal uncle with a history of heart murmur. Proband B was born prematurely at 35 weeks gestation with a prenatally diagnosed complex CHD. A postnatal evaluation revealed right-sided heart defects including pulmonary atresia with intact ventricular septum (PA/IVS), right ventricular hypoplasia, tricuspid valve hypoplasia, hypoplastic main and bilateral branch pulmonary arteries, and possible coronary sinusoids. Cardiac catheterization yielded anatomy and hemodynamics unfavorable to repair. Hence, heart transplantation was indicated. Upon genomic testing, a normal SNP microarray was observed, while trio WES analysis identified a novel heterozygous [Chr18:c.1757C>T (p.Pro586Leu)] variant in the GATA6 gene. This variant was inherited from the father, who carries a clinical diagnosis of tetralogy of Fallot. These findings provide new insights into novel GATA5/6 variants, elaborate on the genotypic and phenotypic association, and highlight the critical role of GATA5 and GATA6 transcription factors in a wide spectrum of right-sided CHDs.

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R01 HL153853 United States HL NHLBI NIH HHS; R25 HD109116 United States HD NICHD NIH HHS; T32 GM008243 United States GM NIGMS NIH HHS; T32GM008243 NIH/NIGMS; R25Actf HD109116Projectf01A1 NIH/NICHHD; 1R01 HL153853-01 NIH/NHLBI

Keywords: GATA; pulmonary valve stenosis; right ventricle hypoplasia; right-sided CHD; transcription factor; whole-exome sequencing; zinc finger-containing protein

0 (GATA6 Transcription Factor)
0 (GATA6 protein, human)
0 (GATA5 Transcription Factor)
0 (GATA5 protein, human)

Date Created: 20250313 Date Completed: 20250313 Latest Revision: 20250512

20250513

PMC11901071

10.3390/ijms26052115

40076735