**Background:** Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder caused by mutations in the GATA3 gene on chromosome 10p14. Only 191 cases have been previously documented. This study reports a novel splice site variant (c.1050+2T>C) in a Chinese patient, investigates its molecular consequences via minigene splicing assays, and provides a comprehensive review of all reported HDR cases to explore genotype-phenotype correlations.
**Methods:** The proband, a 6-year-old girl with seizures since 7 months of age, bilateral sensorineural hearing loss (60 dB right, 40 dB left), hypocalcemia, hyperphosphatemia, and suppressed PTH, underwent targeted next-generation sequencing using a hearing loss panel covering 406 genes including GATA3. Sanger sequencing confirmed the variant in the patient and excluded it in her parents and sibling. A minigene splicing assay was performed by cloning wild-type and mutant GATA3 exon 5 with flanking introns into pcMINI-C vector, transfecting HEK293T and HeLa cells, and analyzing mRNA via RT-PCR and Sanger sequencing. A comprehensive literature review identified 92 articles and 192 patients (including this case) with molecularly confirmed HDR syndrome. Clinical features were stratified by mutation type: missense (n=42), null (frameshift, splice-site, nonsense; n=125), and gross deletion (n=25).
**Key Results:** The patient carried a de novo heterozygous GATA3 c.1050+2T>C variant (intron 5), classified as pathogenic by ACMG (PVS1+PM2_Supporting+PP3+PP4). In silico tools predicted splicing disruption (SpliceAI score 0.96, CADD 33). The minigene assay confirmed retention of 80 bp of intron 5 (c.1050_1051ins80bp), causing a frameshift and premature termination codon (p.Ile351Alafs*14) in both cell lines. The literature review showed that among 192 patients, 71.24% (109/153) presented the classic triad. Hypoparathyroidism occurred in 93.82% (167/178), hearing loss in 98.90% (179/181), and renal lesions in 74.70% (124/166). Seizures were present in 33.53% (56/167) of hypoparathyroid patients, tetany in 17.37% (29/167), and asymptomatic hypoparathyroidism in 37.13% (62/167). Patients with missense variants had significantly more asymptomatic hypoparathyroidism (p < 0.001) than null or gross deletion groups. Age of symptom onset was not significantly different between missense and null groups, but gross deletion patients had earlier onset than missense (p = 0.0157). Hearing loss onset was earlier in null and gross deletion groups compared to missense (p = 0.0224 and 0.0145, respectively). 71.88% (23/32) of pedigrees showed genetic anticipation. Among 103 distinct pathogenic variants identified, 73.79% were in exons, with exons 3 and 4 having high density; 41.18% were novel.
**Clinical Implications:** The c.1050+2T>C variant expands the genotypic spectrum of HDR syndrome and highlights the importance of investigating splice site variants with functional assays, as they can cause truncation even when outside ZnF domains. The delayed diagnosis (from 7 months to 6 years in this case) underscores the need for early genetic testing in children presenting with hearing loss and hypocalcemia. The high rate of asymptomatic hypoparathyroidism (37.13%) necessitates routine biochemical screening. The observed genetic anticipation suggests that clinical severity may worsen across generations, warranting careful family monitoring. The study emphasizes that loss-of-function variants in any region of GATA3 can produce severe phenotypes, and comprehensive management should include hearing aids, calcium/vitamin D supplementation, and renal monitoring.
**Study Limitations:** This is a single case report with in vitro functional validation; the minigene assay was performed in cell lines (HEK293T and HeLa), which may not fully reflect in vivo splicing. The literature review is retrospective and includes potential ascertainment bias, as patients with milder phenotypes may be underdiagnosed. Age of onset data were categorized in some studies, potentially reducing precision. The study did not include functional analysis of the truncated protein at the cellular level.
**Conclusion:** This study identifies a novel de novo GATA3 splice site variant causing HDR syndrome and demonstrates its mechanism through intron retention and truncation. The comprehensive review confirms the classic clinical triad and reveals high prevalence of asymptomatic hypoparathyroidism and genetic anticipation. Early diagnosis via next-generation sequencing is crucial for timely intervention and management.