# De Novo Heterozygous GATA3 Missense Variant Causes an Unexpected Phenotype of Non-Syndromic Hearing Impairment with Apparently Recessive Inheritance

## TL;DR

A new GATA3 gene variant causes non-syndromic hearing loss in two brothers, with the mutation arising de novo in the father's germ line.

## Contribution

Identifies a de novo GATA3 missense variant causing non-syndromic hearing impairment with an apparently recessive inheritance pattern.

## Key findings

- The c.812C>T (p.Ser271Leu) variant in GATA3 was found in two brothers with non-syndromic hearing impairment.
- The variant was confirmed to be de novo in the father's germ line and not inherited from either parent.
- Functional assays supported the pathogenicity of the variant despite no additional clinical features of HDR syndrome.

## Abstract

Hearing impairments (HIs) are clinically and genetically very heterogeneous. Finding the causative mutations in patients is frequently a challenge. We investigated two brothers affected by a sensorineural, moderate non-syndromic HI. Exome sequencing revealed that they carried the heterozygous c.812C>T (p.Ser271Leu) variant in GATA3. This gene encodes a transcription factor involved in embryonic development, its mutations causing the autosomal dominant HDR (hypoparathyroidism, deafness, and renal disease) syndrome. The variant affects a conserved residue within the proximal zinc-finger motif of GATA3. Sanger sequencing confirmed the presence of the variant in the two brothers, but it showed that surprisingly it was not carried by any of the parents. Segregation studies on 20 fully informative microsatellite markers in the family confirmed that the variant arose de novo. A benign SNP in the mother, close to the position of the variant, allowed us to determine that this was inherited from the father. Gene reporter functional assays supported the pathogenicity of the variant. Clinical reassessment of the two brothers did not disclose any additional abnormality. We conclude that mosaicism for this de novo mutation in the father’s germ line explains the pattern of inheritance in this family and that p.Ser271Leu is causing this unexpected phenotype of non-syndromic HI.