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Fetal anomalies v0.2366 GATA5 Krithika Murali edited their review of gene: GATA5: Added comment: 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; Changed rating: AMBER; Changed publications: 28180938, 27066509, 34461831, 30229885, 28285006, 25543888, 25515806, 24796370, 23295592, 23289003, 22961344
Fetal anomalies v0.1262 GATA4 Zornitza Stark Marked gene: GATA4 as ready
Fetal anomalies v0.1262 GATA4 Zornitza Stark Gene: gata4 has been classified as Green List (High Evidence).
Fetal anomalies v0.1262 GATA4 Zornitza Stark Phenotypes for gene: GATA4 were changed from ATRIAL SEPTAL DEFECT TYPE 2 to Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429
Fetal anomalies v0.1261 GATA4 Zornitza Stark Publications for gene: GATA4 were set to
Fetal anomalies v0.1260 GATA4 Zornitza Stark Mode of inheritance for gene: GATA4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1240 GATA4 Ain Roesley reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 12845333, 18055909, 15689439, 33413087, 30455927; Phenotypes: Atrial septal defect 2 MIM#607941, Atrioventricular septal defect 4 MIM#614430, Ventricular septal defect 1 MIM#614429; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.0 GATA4 Zornitza Stark gene: GATA4 was added
gene: GATA4 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: GATA4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: GATA4 were set to ATRIAL SEPTAL DEFECT TYPE 2