GATA3 – Hypoparathyroidism-Deafness-Renal Dysplasia Syndrome

GATA3 haploinsufficiency underlies HDR syndrome, an autosomal dominant disorder characterised by congenital hypoparathyroidism, sensorineural hearing loss and renal dysplasia. Initial deletion‐mapping of chromosome 10p14–pter defined a 200 kb critical region harbouring GATA3; subsequent mutation analysis in three unrelated probands identified nonsense and intragenic deletions predicted to abolish DNA binding (PMID:10935639).

Genetic evidence is robust: autosomal dominant loss‐of‐function variants have been reported in over 65 unrelated probands across multiple cohorts (PMID:10935639; PMID:29663634), including both de novo and familial cases with segregation in nine additional affected relatives (PMID:25771973). A representative variant is c.108_109del (p.Met36IlefsTer16), identified de novo in a 14-year-old with the full HDR triad and basal ganglia calcifications (PMID:19248180).

The variant spectrum is dominated by frameshift and nonsense changes, splice-site mutations and whole‐gene deletions, all predicted to truncate or destabilise the dual zinc‐finger domains of GATA3. No recurrent founder alleles have been noted; instead, a high allelic heterogeneity underscores the gene’s dosage sensitivity.

Functional assays confirm a haploinsufficiency mechanism: truncating mutations abrogate DNA binding and transactivation in electrophoretic mobility shift and luciferase reporter assays (PMID:14985365). In Gata3–/– mice, rescue of embryonic lethality by catecholamine supplementation revealed renal hypoplasia mirroring human HDR, further supporting biological concordance (PMID:10835639).

No conflicting studies disputing the GATA3–HDR association have been reported; phenotypic outliers without GATA3 variants likely reflect genetic heterogeneity of isolated deafness or renal anomalies (PMID:29663634).

Integrating genetic and experimental data, the evidence for GATA3 in HDR syndrome meets ClinGen criteria for a definitive gene–disease relationship. GATA3 testing is clinically indicated in patients presenting with hypoparathyroidism plus either deafness or renal dysplasia. Early molecular diagnosis enables targeted management of calcium homeostasis and renal monitoring.

Key Take-home: GATA3 haploinsufficiency is definitively established as the cause of HDR syndrome, guiding diagnostic testing and patient care.

References

• Nature • 2000 • GATA3 haplo-insufficiency causes human HDR syndrome PMID:10935639
• American Journal of Medical Genetics Part A • 2009 • HDR syndrome: a novel "de novo" mutation in GATA3 gene PMID:19248180
• Mutation Research • 2004 • Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome PMID:14985365
• PLoS Genetics • 2018 • Barakat syndrome revisited PMID:29663634
• Mutation Research • 2000 • Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system PMID:10835639
• Clinical Case Reports • 2015 • Identification of a novel GATA3 mutation in a deaf Taiwanese family by massively parallel sequencing PMID:25771973

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