Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies

Abstract

GATA5 belongs to the GATA family of transcription factors characterized by highly evolutionarily conserved zinc-finger DNA-binding domains. Mouse models have implicated a role of GATA5 during mammalian embryogenesis, including proper heart development and gender-specific regulation of female genitourinary tract formation. Previous studies have found an association of heterozygous missense alterations in GATA5 with a broad variety of heart diseases; however, the clinical relevance of the identified susceptibility variants has remained unclear. Here, we report on a girl with hydrops fetalis, congenital heart defects, clitoromegaly and postnatally increased 17-hydroxyprogesterone levels. By trio whole-exome sequencing, we identified compound heterozygous missense mutations, p.Ser19Trp and p.Arg202Gln, in GATA5 as putative disease-causing alterations. The identified mutations fail to rescue the cardia bifida phenotype in a zebrafish model, mislocalize to subnuclear foci when transiently transfected in HEK293 cells and possess less transcriptional activity. In addition to demonstrating the pathogenicity of identified mutations, our findings show that GATA5 mutations, in addition to heart diseases, can result in congenital abnormalities of the female genitourinary tract in humans.

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next‐generation sequencing

“…18 Very recently, homozygous and compound heterozygous GATA5 variants have been reported to cause, respectively, isolated heart defect in male patients and heart defect with abnormal genitals in a female. 18,31 In our case, GATA5:p (Tyr142His) co- has very recently been associated with diaphragm eventration, 32 a mild form of diaphragmatic defect characterized by diaphragmatic thinning and weakness with and abnormal and dysplastic diaphragmatic muscle. 33 Similarly, homozygous Pbx1 deletion causes CDH with an abnormal muscle patterning and an abnormal Pax3, Myod1,…”

“…Originally, heterozygous GATA5 variants have been described in association with various forms of congenital heart defects with a reduced penetrance in several families . Very recently, homozygous and compound heterozygous GATA5 variants have been reported to cause, respectively, isolated heart defect in male patients and heart defect with abnormal genitals in a female . In our case, GATA5:p (Tyr142His) co‐occurred with nine other VUS in an African patient, suggesting that the associated variants are likely to drive GATA5 phenotypic heterogeneity.…”

Variants in cardiac GATA genes associated with bicuspid aortic valve

“…Moreover, and more importantly, p.Arg202Gln seems to affect organogenesis of the heart, since GATA5 with this variant fail to rescue the cardia bifida phenotype in a model of zebrafish deficient in GATA5. 30 Although this change has been described in ExAC database, it is extremely rare, with a MAF of 0.012% in European (Non-Finnish) population, thus being significantly enriched in our BAV population. In this regard, it is important to remember that, although this database includes individuals without severe paediatric diseases, the possibility that some of the participants may suffer a specific disease cannot be ruled out.…”

“…This variant has been deeply studied from a functional point of view and has been shown to affect the subnuclear localisation and the transcriptional activity of GATA5 in vitro. Moreover, and more importantly, p.Arg202Gln seems to affect organogenesis of the heart, since GATA5 with this variant fail to rescue the cardia bifida phenotype in a model of zebrafish deficient in GATA5 . Although this change has been described in ExAC database, it is extremely rare, with a MAF of 0.012% in European (Non‐Finnish) population, thus being significantly enriched in our BAV population.…”

A system‐based approach to the genetic etiologies of non‐immune hydrops fetalis

“…Cardiac rhabdomyomas are classically associated with tuberous sclerosis, and may present with NIHF . Cardiomyopathy in association with NIHF has been reported with arthrogryposis, mitochondrial disorders such as Barth syndrome, RASopathies such as Noonan and Costello syndrome, lysosomal storage disorders such as mucopolysaccharidosis type VII, and other single gene disorders . Truncus arteriosus and interrupted aortic arch can be seen with NIHF in the setting of 22q11 microdeletion syndrome .…”