Hypoparathyroidism, deafness, and renal dysplasia syndrome: 20 Years after the identification of the firstGATA3mutations

Abstract

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by heterozygous mutations of the GATA3 gene. In the last 20 years, since the identification of the genetic cause of the HDR syndrome, GATA3 mutations have been reported in 124 families (177 patients). The clinical aspects and molecular genetics of the HDR syndrome are reviewed here together with the reported mutations and phenotypes. Reported mutations consist of 40% frameshift deletions or insertions, 23% missense mutations, 14% nonsense mutations, 6% splice‐site mutations, 1% in‐frame deletions or insertions, 15% whole‐gene deletions, and 1% whole‐gene duplication. Missense mutations were found to cluster in the regions encoding the two GATA3 zinc‐finger domains. Patients showed great clinical variability and the penetrance of each HDR defect increased with age. The most frequently observed abnormality was deafness (93%), followed by hypoparathyroidism (87%) and renal defects (61%). The mean age of diagnosis of HDR was 15.3, 7.5, and 14.0 years, respectively. However, patients with whole‐gene deletions and protein‐truncating mutations were diagnosed earlier than patients with missense mutations.

Clinical report of a neonate carrying a large deletion in the 10p15.3p13 region and review of the literature

“…To date, several types of GATA3 mutations related to HDR syndrome have been reported in nearly 124 families (177 patients) worldwide. These include about 40% frameshift deletions or insertions, 23% missense mutations, 14% nonsense mutations, 6% splice site mutations, 1% in-frame deletions or insertions, 15% complete gene deletions, and 1% complete gene duplications [ 21 ]. Vidavalur et al [ 22 ] reported a male premature infant who was small for gestational age, with micrognathia and facial malformation, combined with hypoparathyroidism and bilateral sensorineural hearing loss.…”

Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1

“…Similarly, a missense mutation in GATA3 was present in a family with relatives' ages 15 to 60 years with apparently non‐syndromic hearing loss. Ages at onset of the syndromic features of GATA3 are variable, with mean age of onset during childhood or early teenage years, but possible onset of the full spectrum of phenotypes as late as age 50 57 . It is still possible, therefore, that the affected relatives of this family will develop syndromic features.…”

Synergistic role of retinoic acid signaling and Gata3 during primitive choanae formation

“…Previous reports have shown that Gata3 loss-of-function in mice results in early lethality around E11 with severe defects including craniofacial anomalies (21,22). In addition, GATA3 mutations in human result in hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, a constellation of anomalies that also includes craniofacial defects such as CA (8,23). The fact that Gata3 is strongly expressed around the developing frontonasal process in combination with its connection to human disease motivated us to investigate the role of Gata3 in CA and its association with retinoid signaling (24).…”