GATA3 abnormalities and the phenotypic spectrum of HDR syndrome

We report on GATA3 analysis and the phenotypic spectrum in nine Japanese fa milies with the HDR syndrome (hypoparathyroidism, sensorineural deafness, a nd renal dysplasia) (MIM 146255). Fluorescence in situ hybridisation and mi crosatellite analyses showed heterozygous gross deletions including GATA3 i n four families. Sequence analysis showed heterozygous novel mutations in t hree families: a missense mutation within the first zinc finger domain at e xon 4 (T823A, W275R), an unusual mutation at exon 4 (900insAA plus 90linsCC T or C901AACCCT) resulting in a premature stop at codon 357 with loss of th e second zinc finger domain, and a nonsense mutation at exon 6 (C1099T, R36 7X). No GATA3 abnormalities were identified in the remaining two families. The triad of HDR syndrome was variably manifested by patients with GATA3 ab normalities. The results suggest that HDR syndrome is primarily caused by G ATA3 haploinsufficiency and is associated with a wide phenotypic spectrum.