Congenital Heart Defects, Multiple Types, 5

A number sign (#) is used with this entry because of evidence that multiple types of congenital heart defects (CHTD5) are caused by heterozygous mutation in the GATA5 gene (611496) on chromosome 20q13. Biallelic mutations have been reported in 2 patients (see MOLECULAR GENETICS).

For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.

Clinical Features

Jiang et al. (2013) reported 4 Han Chinese probands with congenital heart disease and mutations in the GATA5 gene, 3 of whom had affected family members. Cardiac defects included atrial septal defect (ASD), ventricular septal defect (VSD), double-outlet right ventricle (DORV), tetralogy of Fallot (TOF), and aortic stenosis (AS). Intrafamilial phenotypic variability was demonstrated in 1 family (family 2), in which affected members had VSD, DORV, and/or TOF. Atrial fibrillation (AF) was also documented in 2 affected members of 1 of the families.

Wei et al. (2013) studied a Han Chinese family in which 5 members over 3 generations had subarterial VSD. In addition, 2 of the affected individuals had DORV, and 1 had AS.

Shi et al. (2014) reported 2 Han Chinese families segregating autosomal dominant bicuspid aortic valve (BAV) and mutations in the GATA5 gene. Affected family members also exhibited other cardiac defects, including VSD and AS, and 2 patients had documented AF.

Inheritance

Jiang et al. (2013) reported 4 affected members over 3 generations of a Han Chinese family with multiple types of congenital heart defects and heterozygous mutations in the GATA5 gene, consistent with autosomal dominant inheritance.

Two patients with biallelic mutations in GATA5 have been reported (see MOLECULAR GENETICS).

Molecular Genetics

In a cohort of 130 unrelated Han Chinese patients with familial AF, Yang et al. (2012) sequenced the GATA5 gene and identified heterozygous missense mutations in 3 of the probands. Congenital heart disease was documented in affected members of 2 of the families, including ASD and VSD. The mutations segregated fully with disease in 2 of the families; in the third family, the youngest mutation-positive individual did not show AF on a 24-hour monitoring, which the authors noted might have been an insufficient length of time to detect paroxysmal AF. Functional analysis of the variants was not reported. The authors concluded that GATA5 variants predispose to AF.

In a cohort of 110 unrelated Han Chinese patients with familial AF, Gu et al. (2012) sequenced the GATA5 gene and identified heterozygous missense mutations in 2 of the probands. The presence or absence of structural cardiac defects in affected family members was not reported. The mutations, which segregated with disease in the families and were not found in controls or public variant databases, showed significantly reduced transcriptional activation compared to wildtype GATA. The authors concluded that dysfunctional GATA5 confers susceptibility to AF.

In a cohort of 320 unrelated Han Chinese patients with congenital heart disease, Jiang et al. (2013) analyzed the GATA5 gene and identified heterozygous missense mutations (see, e.g., 611496.0001) in 4 probands. The mutations segregated fully with disease in 3 of the families, and none of the mutations were found in 200 ethnically matched controls. In 1 family, the proband inherited the mutation from her apparently unaffected father, which the authors stated might be due to spontaneous closure of a minor cardiac defect, incomplete penetrance, or epigenetic or environmental factors.

In a cohort of 120 unrelated Han Chinese patients with VSD, Wei et al. (2013) sequenced the GATA5 gene and identified 1 proband with a heterozygous missense mutation (L199V; 611496.0002). The mutation segregated fully with disease in the family and was not found in 200 ethnically matched controls or the dbSNP database. Functional analysis demonstrated significantly reduced transcriptional activation with the L199V mutant compared to wildtype GATA5, and the mutant showed a dominant-negative effect on the wildtype protein.

In a cohort of 118 unrelated Han Chinese patients with lone AF, Wang et al. (2013) sequenced the GATA5 gene and identified 1 proband with a heterozygous missense mutation (W200G; 611496.0003). The mutation segregated fully with disease in the proband's family and was not found in controls. ASD had been documented in 2 affected family members, and the authors noted that other affected family members might have had cardiac structural defects that closed spontaneously after birth.

In a cohort of 110 unrelated Han Chinese patients with BAV, Shi et al. (2014) sequenced the GATA5 gene and identified 2 probands with a heterozygous missense mutation (see, e.g., 611496.0004). The mutations segregated fully with disease in each family and neither was found in 200 ethnically matched controls or in public variant databases. Affected family members also exhibited other cardiac defects, including VSD and AS, and 2 patients had documented AF.

In a cohort of 130 unrelated Han Chinese patients diagnosed with dilated cardiomyopathy (CMD), Zhang et al. (2015) analyzed the GATA5 gene and identified a heterozygous missense mutation that segregated with disease in 1 family, in which 2 affected members also had VSD, 1 had atrioventricular block, and 1 had paroxysmal atrial fibrillation.

Possible Biallelic Inheritance

In 185 consecutive pediatric or adolescent Lebanese patients with a diagnosis of congenital heart disease, Kassab et al. (2016) screened the GATA4 (600576), GATA5, and GATA6 (601656) genes and identified 8 missense variants in GATA5, only 1 of which appeared potentially pathogenic: a Y142H (rs111554140) substitution that was found in homozygosity in a patient with DORV, VSD, and mild pulmonary stenosis (PS). The healthy parents, who had normal cardiac structure and function on echocardiography, were heterozygous for the variant, which was not found in 150 Lebanese controls but was present in the ExAC database with a minor allele frequency (MAF) of 0.002035. Functional analysis showed that the Y142H mutant had approximately one-third of the transactivation activity of the wildtype protein. The authors noted that Y142H had previously been reported by Padang et al. (2012) in heterozygosity in a Caucasian man with apparently sporadic BAV, who underwent aortic valve replacement at age 28 years for severe aortic stenosis, as well as ascending aorta replacement at age 58 for progressive aneurysm.

Hempel et al. (2017) studied a 2-year-old girl, born of a dichorionic diamniotic twin pregnancy, who had hydrops fetalis and ascites as well as VSD, ASD, and patent ductus arteriosus (PDA), and developed mild hypertrophic cardiomyopathy within the first few weeks of life. She also showed clitoromegaly with signs of virilization, and had cysts on the right ovary and a gallstone. Trio whole-exome sequencing of the proband and her parents revealed compound heterozygosity for missense mutations in the GATA5 gene, S19W and R202Q, in the proband. Her unaffected parents were each heterozygous for 1 of the mutations, as was her healthy twin sister. The authors noted that the S19W variant had previously been reported in a 28-year-old man with apparently sporadic BAV and trivial regurgitation by Padang et al. (2012). Both variants were present in heterozygosity in the ExAC database, with MAFs of 0.02069 and 0.00006955 for S19W and R202Q, respectively. Functional analysis demonstrated that neither variant could rescue the cardia bifida phenotype in gata5-deficient zebrafish morphants, and both showed mislocalization and reduced transcriptional activity compared to wildtype GATA5. Endocrinologic evaluation in the 2-year-old proband revealed elevated 17-hydroxyprogesterone levels. Noting that GATA5 was known to regulate expression of the progesterone receptor (Huggins et al., 2006), Hempel et al. (2017) suggested that the patient's clitoromegaly and elevated 17-hydroxyprogesterone levels might have resulted from aberrant regulation of progesterone levels and signaling during embryogenesis.