Congenital Heart Defect

Gene: GATA5

I don't know

Variants in GATA5 have been reported in relation to a range of congenital heart conditions, including bicuspid aortic valve (BAV; highest number of publications associated), ascending aortic aneurysm, familial atrial fibrillation, Tetralogy of Fallot, and familial dilated cardiomyopathy

GATA5 is thought to play a critical role in aortic valve formation. In mice, targeted deletion of Gata5 leads to hypoplastic hearts and partially penetrant BAV formation (PMID: 21633169), and GATA5 may interact with GATA4 and GATA 6 as compound Gata4/Gata5 and Gata5/Gata6 mutants die embryonically or perinatally due to severe congenital heart defects (PMID: 21839733).

The mechanism of pathogenicity is not clear; both changes that result in significant increases or decreases in GATA5 activity have been associated with congenital heart disease.

-Compared to wildtypes, Atrial natriuretic factor (ANF)-luciferase reporter gene assay have associated GATA5 variants with significantly reduced activation activity in Tetraology of Fallot (PMID: 23289003), congenital ventriculoseptal defect (PMID 22961344), congenital BAV (PMID: 24638895), and familial atrial fibrillation (PMID: 2329559).

- However, Ackerman (2012) found that GATA variants (c.8A>G (p.Gln3Arg) shows gain of function (luciferase reporter assay under the control of the VEGF-A promoter. PMID: 23040494). Shan et al (2014; PMID 25515806) found that, in cultured cardiomyocytes, transcriptional activities of the GATA5 gene promoter were significantly decreased with one variant (g.61051165A>G) and increased in another (g.61051463delC) compared to empty vectors as negative controls (genomic build not reported. PMID: 25515806).

Both AR and AD cases have been reported, as reviewed below:
- AR: PMID 28180938 Hempel et al 201; PMID: 27066509 Kassab et al 2015
- AD: PMID 34461831 Ma et al 2021; PMID: 30229885 Alonso-Montes et al 2018; Zhang et al 2015 PMID 25543888; Shan et al 2014 PMID 25515806; PMID 24796370 Bonachea et al 2014; PMID: 23289003 Wei et al 2013; Wei et al Pediatric Cardiology 2013 PMID 22961344

In addition to the cases already reviewed:

PMID: 35534675 Jaouadi et al (2022; case-level data) reported heterozygous NM_080473: exon2, c.8A>G: p.(Gln3Arg) variants in two brothers with BAV and ascending aortic aneurysm, but the sister with BAV without aneurythm did not have the same variant, and neither did the unaffected brother. The author noted that this variant has been reported only in male cases.

PMID 22641149: Padang et al (2012; case-control data) reported the same variant c.8A>G: p.(Gln3Arg) as 1 of 4 rare non-synonymous variations within the GATA5 transcriptional activation domains, from 100 unrelated, non-syndromic, sporadic and familial cases of BAV, with or without its associated aortopathy (comparison: 160 predominantly Caucasian controls, as well as other populational databases). No additional supporting functional studies were reported.

PMID: 26708639 Dargis et al (2016; case-control data), found two GATA5 variants that were considered potentially pathogenic (determined using C-Score (CADD) >10): g.61041653G>C intronic variant in 28/48 patients with BAV, and 1/48 patient with g.61039662 T > C 3’UTR variant (hg19). No additional functional data were included.

PMID: 24638895 Shi et al (2014; case-level data), found 2 heterozygous GATA variants in 2/110 unrelated patients with BAV. In the first family, variant c.46T>G: p.Y16D, segregated in 2 family members (affected brother and son) and was not present in 5 other unaffected family members). In family 2, variant c.754A>C: p.T252P, segregated in an affected son (not present in two other unrelated family members). Functional studies: found reduced transcriptional activity, where both mutants (Q13R or T252P), alone or in combination, had significantly reduced transcriptional activity than wildtype.

Created: 14 Nov 2023, 10:56 a.m. | Last Modified: 14 Nov 2023, 10:56 a.m.

Panel Version: 0.313

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
617912

Publications

• 21633169
• 21839733
• 23289003
• 22961344
• 24638895
• 2329559
• 23040494
• 25515806
• 35534675
• 22641149
• 26708639

I don't know

OMIM gene disease association for multiple congenital heart defects both AR and AD inheritance

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AR inheritance - x2 patients with congenital heart disease

PMID 28180938 Hempel et al 2017 - x1 DCDA twin female born at 28+6 weeks after PROM. Ascites, non-immune hydrops fetalis and VSD diagnosed prenatally at 20 weeks. Postnatally diagnosed with ASD, PDA, mild HCM and gallstones. Hydrops likely secondary to congenital heart disease. Also diagnosed with clitoromegaly with transient elevation in 17-hydroxyprogrogesterone till 10 weeks of age and normal adrenal androgen levels. 46 XX confirmed on karyotype. Proband compound het for paternally inherited GATA 5 c.56G > C, p.Ser19Trp variant and maternally inherited c.605C > T, p.Arg202Gln. Carrier arents and twin sister with c.605C > T, p.Arg202Gln unaffected. Arg202Gln absent from population database, p.Ser19Trp - 241 hets in gnomad not seen in homozygous form.

Supportive zebrafish models for GATA5 LoF. Previous mouse models suggest that GATA5 plays a role during mammalian embryogenesis, including heart developmen and progesterone receptor expression.

PMID: 27066509 Kassab et al 2015

Lebanese patient cohort with high rates of consangunity. A total of 185 patients with different forms of congenital heart disease (CHD)were screened for GATA4, GATA5, GATA6 variants + 150 healthy individuals. 2 patients with homozygous GATA5 varianst identified. One patient wtih aortic stenosis, coarctation of the aorta, VSD, PDA with homozygous p.T67P variants - in silicos benign, gnomad 4975 hets and 402 homozygotes. Another patient with double outlet right ventricle / ASD / pulmonary stenosis and homozygous p.Y142H – present in gnomad 39 hets, 0 homozygotes, unaffected consanguineous carrier parents.

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Multiple studies reporting AD inheritance for bicuspid aortic valve, congenital heart disease, DCM, AF - evidence conflicting

PMID 34461831 Ma et al 2021 BMC Cardiovascular Disorders - prospective recruitment of 130 unrelated patients with bicuspid aortic valve with complex congenital heart disease being one of the exclusion criteria. 2 heterozygous GATA5 variants identified present in population database. No segregation data.

PMID: 30229885 Alonso-Montes et al 2018, European Journal of Clinical Investigations - North of Spain cohort. 122 unrelated patients with bicuspid and 154 unaffected patients had GATA4, GATA5 and GATA6 sequencing. Missense p.Arg202Gln in GATA5 identified, absent from gnomad, in-silicos probably damaging, no segregation data.

Zhang et al 2015 PMID 25543888 - DCM cohort heterozygous GATA5 c.719G>A p.G240D identified in a family. Authors report co-segregation with DCM in multiple family members with associated VSD in 2 individuals, functional analyses showed diminished transcriptional activity. In-silicos predict possibily damaging. Variant absent from gnomad but in a region of low exome coverage

Shan et al 2014 PMID 25515806 - analysis of GATA5 gene promoter in 343 patients with VSD and 348 controls. Two novel variants reported in affected individuals but also present in unaffected parents.

PMID 24796370 Bonachea et al 2014 - Cohort of 78 bicuspid aortic patients (50 with isolated BAV and 28 with associated aortic coarctation) had GATA5 sanger sequencing analysis. x2 variants identified. p.Gln3Arg variant present in 447 hets in gnomad – inherited from unaffected mother, p.Leu233Pro – present in 359 hets – apparently de novo

PMID: 23289003 Wei et al 2013 Int Journal Medical Science - cohort of 130 unrelated patients with TOF and 200 unrelated controls. GATA5 c.559C>G p.R187G variant identified in affected individual – although variant absent from gnomad alternative aa change at same position present in gnomad including truncating frameshift variants. GATA5 c.620A>G p.H207R – absent from gnomad. Authors report co-segregation of both variants with TOF in multiple family members, some with additional congenital heart defects.

Wei et al Pediatric Cardiology 2013 PMID 22961344 - GATA5 sequenced in 120 unrelated patients with VSD and 200 controls. Heterozygous GATA5 variant p.L199V identified in a patient with VSD. Author reports co-segregation in multiple affected family members. Variant absent from gnomad with X1 synonymous het variant only at same position

Created: 17 Jan 2022, 12:36 p.m. | Last Modified: 17 Jan 2022, 12:36 p.m.

Panel Version: 0.168

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Congenital heart defects, multiple types, 5 - #617912

Publications

• 28180938
• 27066509
• 34461831
• 30229885
• 28285006
• 25543888
• 25515806
• 24796370
• 23295592
• 23289003
• 22961344