Journal Article

Temperature-Sensitive Auditory Neuropathy: Report of a Novel Variant of OTOF Gene and Review of Current Literature

Bertini, Veronica, Bruschini, Luca, Forli, Francesca, Romano, Silvia, Capobianco, Silvia, Lazzerini, Francesco, Fogli, Antonella, Berrettini, Stefano

2023

Overview

Background and objectives: Otoferlin is a multi-C2 domain protein implicated in neurotransmitter-containing vesicle release and replenishment of the cochlear inner hair cell (IHC) synapses. Mutations in the OTOF gene have been associated with two different clinical phenotypes: a prelingual severe-to-profound sensorineural hearing loss (ANSD-DFNB9); and the peculiar temperature-sensitive auditory neuropathy (TS-ANSD), characterized by a baseline mild-to-moderate hearing threshold that worsens to severe-to-profound when the body temperature rises that returns to a baseline a few hours after the temperature has fallen again. The latter clinical phenotype has been described only with a few OTOF variants with an autosomal recessive biallelic pattern of inheritance. Case report: A 7-year-old boy presented a picture compatible with TS-ANSD exacerbated by febrile states or physical exercise with mild-to-moderate hearing loss at low and medium frequencies and a decrease in speech discrimination that worsened with an unfavorable speech-to-noise ratio. Otoacoustic emissions (OAEs) were present whereas auditory brainstem responses (ABRs) evoked by a click or tone-burst were generally absent. No inner ear malformations were described from the CT scan or MRI. Next-generation sequencing (NGS) of the known deafness genes and multi-phasic bioinformatic analyses of the data detected in OTOF a c.2521G>A missense variant and the deletion of 7.4 Kb, which was confirmed by array-comparative genomic hybridization (array-CGH). The proband’s parents, who were asymptomatic, were tested by Sanger sequencing and the father presented the c.2521G>A missense variant. Conclusions: The picture presented by the patient was compatible with OTOF-induced TS-ANSD. OTOF has been generally associated with an autosomal recessive biallelic pattern of inheritance; in this clinical report, two pathogenic variants never previously associated with TS-ANSD were described.

• Publisher: MDPI AG,MDPI
• Subject: Age / Analysis / Audiometry / Body temperature / Care and treatment / Case Report / Child / Comparative Genomic Hybridization / Deafness / Diagnosis / DNA sequencing / Fever / Genetic aspects / Genomics / Hearing loss / Hearing Loss, Central - genetics / Hearing Loss, Sensorineural - genetics / Humans / Male / Membrane Proteins - genetics / Methods / Mutation / Neurotransmitters / Nucleotide sequencing / OTOF / otoferlin / Phenotype / Signal to noise ratio / Speech / Synapses / targeted next-generation sequencing / Temperature / temperature-sensitive auditory neuropathy