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Kidney Week

Abstract: PO1285

HDR: A Novel Mutation in GATA-3 with Variable Expressivity in an Affected Family

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Sambharia, Meenakshi, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States
  • Misurac, Jason, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States
  • Thomas, Christie P., The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States
Introduction

Hypoparathyroidism, deafness, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disorder caused by heterozygous variants in GATA-3. GATA-3 belongs to a family of dual zinc finger transcription factors that is involved in embryonic development of the inner ear, kidneys, and parathyroids. The exact prevalence of HDR syndrome is unknown, but less than 200 cases have been described. The disease has variable expressivity even within the same family. Making a diagnosis can be challenging, more so in individuals with no laboratory abnormalities. Herein we describe a father-daughter dyad with HDR syndrome with variable disease expression.

Case Description

A 7-year-old female with history of congenital deafness, multicystic dysplastic kidney, reflux nephropathy, and multiple urinary tract infections underwent genetic testing. Exome sequencing revealed a heterozygous missense variant in GATA-3, a threonine to arginine substitution (c.1058G>C, p.Arg353Thr). The missense variant was ultrarare, predicted pathogenic, and classified as likely pathogenic. Laboratory evaluation demonstrated hypoparathyroidism with hypocalcemia and hyperphosphatemia, fulfilling all criteria for HDR syndrome. Calcium levels normalized on calcium and calcitriol supplementation. Cascade screening revealed that her father carried the same genetic variant. Father’s history was pertinent for sensorineural hearing loss diagnosed at 2 years of age with normal renal function, serum calcium, and PTH.

Discussion

Hypoparathyroidism is the most specific symptom of HDR syndrome, absent in 5-7% of affected patients, whereas sensorineural hearing loss is present in 96% of affected patients. Kidney manifestations are variable and may include aplasia, hypoplasia, dysplasia, cysts, vesicoureteral reflux, hematuria, and/or proteinuria. The missense variant described in our patient has not been previously reported, although an alternate amino acid change at the same residue has been reported with HDR syndrome. As the father had isolated deafness, he remained undiagnosed for almost 25 years, until the identification of HDR syndrome in his daughter. Screening family members is important for recognition and treatment of hypoparathyroidism and of renal disease as patients are at risk of symptomatic hypocalcemia and progressive kidney disease.