Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

Abstract

Sensorineural hearing loss is one of the most common inherited sensory disorders. Functional classifications of deafness genes have shed light on genotype- and mechanism-based pharmacological approaches and on gene therapy strategies. In this study, we characterized the clinical phenotypes and genotypes of non-syndromic deafness caused by transcription factor (TF) gene variants, one of the functional classifications of genetic hearing loss. Of 1280 probands whose genomic DNA was subjected to molecular genetic testing, TF genes were responsible for hearing loss in 2.6%. Thirty-three pathogenic variants, including nine novel variants, accounting for non-syndromic deafness were clustered in only four TF genes (POU3F4, POU4F3, LMX1A, and EYA4), which is indicative of a narrow molecular etiologic spectrum of TF genes, and the functional redundancy of many other TF genes, in the context of non-syndromic deafness. The audiological and radiological characteristics associated with the four TF genes differed significantly, with a wide phenotypic spectrum. The results of this study reveal the genetic load of TF gene alterations among a cohort with non-syndromic hearing loss. Additionally, we have further refined the clinical profiles associated with TF gene variants as a basis for a personalized, genetically tailored approach to audiological rehabilitation.

Keywords

• transcription factor variants (TF)
• non-syndromic hearing loss
• <i>POU3F4</i>
• <i>POU4F3</i>
• <i>LMX1A</i>
• <i>EYA4</i>