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

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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 hypoparathyroidism, deafness and renal dysplasia 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.
Funding Information
  • National Institute for Health Research (NIHR Oxford Biomedical Research Centre Programme, NIHR Senior Investigator Award)
  • Wellcome Trust (Wellcome Trust Investigator Award)
  • Fundação para a Ciência e a Tecnologia (UIDB/00709/2020)

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