systematic literature review has been completed

Gene mutations account for more than 60% of congenital sensorineural hearing loss (SNHL) in Western Countries. Hereditary SNHL does not necessarily start at birth, however, as many causative gene mutations only begin to express at much later ages, such as for example DFNA9, also known as the ninth discovered autosomal dominant SNHL.

It is characterized by a late onset of rapid progressive SNHL together with accompanying vestibular impairment. The first reported DFNA9 patients were carrying the c.151 C>T mutation in COCH, which is the result of a substitution of cytosine by thymine nucleotide of the 151th base pair (c.151C>T). At protein level, this missense point mutation induces a mistranslation to a serine instead of a proline amino-acid (p.Pro51Ser, (P51S)), producing mutant cochlin that cause a dominant negative effect due to misfolding.

In the perspective of promising future hearing and vestibular treatment developments, such as gene therapy, stem cell therapy, neural regeneration, in association with cochlear and/or vestibular implantation, a more accurate understanding of the onset of the very first signs of the auditory and vestibular deterioration is important. However, in early stages these first signs of impairment are very discrete and pre-symptomatic.

The aim of this systematic review is to identify studies related to DFNA9, caused by the P51S COCH variant, describing detailed genotype-phenotype correlation in relation to the age and to investigate the age of onset of the SNHL and peripheral vestibular function as well as their progression in relation to age.

The strategy and methodology used for the systematic review was based on the PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analysis Medline, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ISI Web of Knowledge and Web of Science were searched. Information was retrieved about COCH mutations causing DFNA9, including phenotype, genotype, audiometric and vestibular data.

Audiometric data were collected using individual measurements or pure tone average incides in the selected records.In case of different audiometric data presentation, for instance audiograms or different pure tone average (PTA) plots against age, a comprehensive assessment and inventory of all individual measurements was conducted. All available measurements at both ears per frequency were inventoried and a binaural mean value for each frequency per age was averaged, before the calculation of the indices. If longitudinal measurements of the same individual were shown, all the available data was included in the assessment.

The following parameters for the audiometric data were inventoried: pure tone average (PTA), Annual Threshold detarioration (ATD) per frequency and/or PTA, Age-related Typical Audiogram (ARTA) and age of onset of the sensorineural hearing loss (SNHL).

For the vestibular function, all different parameters of the vestibular function were inventoried. Normative values, if mentioned, were used to evaluate the measurements. An overall inventory of all individual vestibular measurements in relation to age was conducted.

The following parameters for the vestibular function were inventoried: Time Constant (T) derived from velocity-step test (VST) in seconds, Caloric response gain on electronystagmography, Annual vestibular deterioration rate and age of onset of vestibular dysfunction.

Inclusion Criteria:

• P51S carriership

Exclusion Criteria:

• no P51S carriership

all affected subjects carrying the P51S COCH mutation