A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

Electrocochleography: New Uses for an Old Test and Normative Values.

Purpose This article combines the results of 3 studies that were presented at the HeAL 2018 Conference in Lake Como, Italy, in June 2018. Each study involved electrocochleography (ECochG), a neurodiagnostic evaluation that has been used clinically for over 80 years but whose applications continue to expand. The 1st study describes recent research wherein ECochG was recorded from asymptomatic subjects who were siblings or offspring of patients with a confirmed diagnosis of Ménière's disease (MD). Our results provide evidence that ECochG may be helpful in not only diagnosing MD but also predicting it as well. Second, case studies are described where ECochG was important in both diagnosing superior semicircular canal dehiscence and monitoring the repair of this condition during surgery. Finally, although ECochG has been practiced clinically for over 8 decades, the protocols for recording, measuring, and interpreting the electrocochleogram continue to lack standardization among clinicians and scientists. We thus present normative data for some of these features based on noninvasive recordings made from the tympanic membrane from 100 normal hearing subjects. Conclusions Although the primary use of ECochG continues to be in the diagnosis of MD, we report on 2 additional clinical applications for this important test of inner ear/auditory nerve function. First, a preliminary study on a small sample of subjects indicates that ECochG may also be useful in predicting MD prior to the onset of symptoms in individuals who may be genetically predisposed to developing it. Second, through a series of case studies, we demonstrate how ECochG is used to help diagnose superior semicircular canal dehiscence and monitor the status of the inner ear during the surgical repair of this condition. Finally, normative values for clinically important components of the electrocochleogram based on tympanic membrane recordings have been established from a large sample of subjects.