Clinical and genetic characteristics of hypoparathyroidism, deafness, and renal dysplasia syndrome in a chronic kidney disease cohort

BACKGROUND: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by GATA-binding protein 3 (GATA3) haploinsufficiency. Although the clinical triad is well recognized, the phenotype is often incomplete, making clinical diagnosis challenging. This study aimed to elucidate the clinical and genetic characteristics of HDR syndrome in a kidney disease cohort. METHODS: We retrospectively analyzed patients with absent or mild urinary abnormalities who underwent genetic testing for chronic kidney disease (CKD) between 2010 and 2025. Targeted next-generation sequencing-based kidney disease panels were used, and copy number variations were assessed using array comparative genomic hybridization. RESULTS: Among 1254 families with CKD, pathogenic or likely pathogenic GATA3 variants were identified in 10 patients (seven families). One additional patient with a clinically compatible phenotype carried a missense variant of uncertain significance. The median age at diagnosis was 5 years (IQR, 2-23; range, 0.7-44 years). GATA3 variants included missense (n = 3, including one variant of uncertain significance), nonsense (n = 2), short insertion/deletion (n = 2), and a whole-gene deletion (n = 1). Regarding the classical triad, hypoparathyroidism, deafness, and renal anomalies were observed in 45, 100, and 90% of patients, respectively. Only 40% exhibited the complete triad, whereas half presented deafness and renal manifestations. CONCLUSIONS: HDR syndrome identified in kidney disease cohorts often presents with incomplete clinical features. In patients with CKD and sensorineural deafness, HDR syndrome should be considered, and comprehensive genetic testing, including copy number analysis, is essential for accurate diagnosis.