Diagnosing Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome and a Novel GATA3 Variant.

Abstract

Hypoparathyroidism (hypoPTH), sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant condition with approximately 200 cases published. HDR syndrome is caused by variants of GATA binding protein 3 gene (GATA3), which encodes a transcription factor, with multiple types of GATA3 variants reported. We present the case of a 76-year-old woman who was diagnosed with hypoPTH when she was aged 40 years and transferred care to our institution. Further history elucidated presence of deafness at age 1 year and chronic kidney disease with a left atrophic kidney diagnosed in her 60 seconds. Genetic testing identified a novel GATA3 missense variant of unknown significance (c.791G > A, p.Cys264Tyr). There was no family history of hypoPTH, deafness, or renal disease, which might indicate incomplete penetrance or de novo mutation. Advanced modeling of protein sequence and biophysical properties predicts abnormal protein function, suggesting possible pathogenicity. In addition, a likely pathogenic variant in the same amino acid was previously described in a patient with HDR, supporting the in silico prediction of pathogenicity in our patient's variant. Syndromic hypoPTH should be considered in patients even if presenting later in life with presumed chronic isolated conditions. Genetic testing can guide further disease screening and family testing when appropriate.