[Analysis of clinical diagnosis, treatment, and pathogenic variants of hypoparathyroidism- sensorineural deafness-renal dysplasia (HDR) syndrome].

Objective

This study aimed to identify pathogenic variants in patients with hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome through whole-exome sequencing (WES), to elucidate the genotype-phenotype correlations, and to provide a basis for refining its clinical diagnostic criteria and genetic counseling.

Methods

Three pedigrees presenting with hypoparathyroidism, sensorineural hearing loss, and renal dysplasia, who visited the First Affiliated Hospital of Zhengzhou University between January 2022 and January 2025, were enrolled. Clinical and genetic data from the probands and their family members were systematically collected. Variant screening was performed on the probands using whole-exome sequencing (WES). Detected variants were evaluated through bioinformatic analysis, validated by Sanger sequencing for segregation within the families, and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. A genotype-phenotype analysis of HDR syndrome was further conducted through a comprehensive literature review.

Results

A total of 5 patients with HDR syndrome were diagnosed across the three pedigrees. The most common clinical phenotypes included sensorineural hearing loss (5/5), hypoparathyroidism (2/5), renal abnormalities (1/5), and preauricular fistula (1/5). Three novel pathogenic variants in the GATA3 gene were identified: c.24_27del (p.Arg9GlyfsTer2), c.681del (p.Glu228SerfsTer38), and c.759_762del (p.Lys254ProfsTer11). These variants had not been previously reported in public databases. Segregation analysis within the families confirmed their complete co-segregation with the disease phenotype, and all were classified as pathogenic according to ACMG guidelines.

Conclusions

We report three novel pathogenic GATA3 variants for the first time, which expands the molecular diagnostic spectrum of HDR syndrome and provides molecular evidence for family genetic counseling and prenatal diagnosis. The combined use of WES and Sanger sequencing effectively improves the diagnostic yield for hereditary hearing loss, particularly in syndromic forms. Furthermore, a phenotype-driven targeted analysis strategy holds significant value in enhancing the detection rate of causative genes.