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

被引：0

作者：

Zodanu, Gloria K. E. ^{[1
,2
]}

Hwang, John H. ^{[1
,2
]}

Mudery, Jordan ^{[1
,2
]}

Sisniega, Carlos ^{[1
,2
]}

Kang, Xuedong ^{[1
,2
]}

Wang, Lee-Kai ^{[3
]}

Barsegian, Alexander ^{[1
,2
]}

Biniwale, Reshma M. ^{[2
,4
]}

Si, Ming-Sing ^{[4
]}

Halnon, Nancy J. ^{[2
]}

UCLA Congenital Heart Defects BioCore Fac, Wayne W.

Grody, Wayne W. ^{[2
,3
,5
]}

Satou, Gary M. ^{[2
]}

Van Arsdell, Glen S. ^{[2
,4
]}

Nelson, Stanly F. ^{[2
,3
,5
]}

Touma, Marlin ^{[1
,2
,6
,7
,8
,9
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Neonatal Congenital Heart Lab, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Childrens Discovery & Innovat Inst, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Eli & Edyth Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Cardiovasc Res Labs, Los Angeles, CA 90095 USA

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2025年 / 26卷 / 05期

关键词：

GATA; transcription factor; zinc finger-containing protein; pulmonary valve stenosis; right-sided CHD; right ventricle hypoplasia; whole-exome sequencing; OF-FUNCTION MUTATIONS; TRANSCRIPTION FACTORS; DOWN-SYNDROME; TETRALOGY; GENETICS; GATA-6; ASSOCIATION; EXPRESSION; EVOLUTION; INSIGHTS;

D O I：

10.3390/ijms26052115

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：18