Detailed Clinical Features of Deafness Caused by a Claudin-14 Variant

Abstract

Tight junctions are cellular junctions that play a major role in the epithelial barrier function. In the inner ear, claudins, occludin, tricellulin, and angulins form the bicellular or tricellular binding of membrane proteins. In these, one type of claudin gene, CLDN14, was reported to be responsible for human hereditary hearing loss, DFNB29. Until now, nine pathogenic variants have been reported, and most phenotypic features remain unclear. In the present study, genetic screening for 68 previously reported deafness causative genes was carried out to identify CLDN14 variants in a large series of Japanese hearing loss patients, and to clarify the prevalence and clinical characteristics of DFNB29 in the Japanese population. One patient had a homozygous novel variant (c.241C>T: p.Arg81Cys) (0.04%: 1/2549). The patient showed progressive bilateral hearing loss, with post-lingual onset. Pure-tone audiograms indicated a high-frequency hearing loss type, and the deterioration gradually spread to other frequencies. The patient showed normal vestibular function. Cochlear implantation improved the patient's sound field threshold levels, but not speech discrimination scores. This report indicated that claudin-14 is essential for maintaining the inner ear environment and suggested the possible phenotypic expansion of DFNB29. This is the first report of a patient with a tight junction variant receiving a cochlear implantation.

Keywords: CLDN14; Claudin-14; cochlear implantation; hearing loss; tight junction; vestibular function.

Figure 1

Pedigree and CLDN14 variants of the family. (A) Pedigree shows autosomal recessive inherited hearing loss (HL), (B) the electropherograms of this family. Target genome enrichment for 68 previously reported deafness causative genes and massively parallel DNA sequencing are carried out for this proband (III-4). Sanger sequencing is used for family segregation analysis. Genetic analysis results are shown under the proband and family members.

Figure 2

Location of pathogenic variants in Claudin-14. Red colored amino acid residues indicate previously reported claudin-14 variants. The blue colored residue indicates the positions of CLDN14 p.Arg81His and p.Arg81Cys.

Figure 3

(A) Pure-tone audiometry (PTA) shows bilateral progressive sensorineural hearing loss in the proband. After a cochlear implantation (CI) in the right ear, sound field hearing threshold tests with a CI show 40 dBSPL. Red: right ear, Blue: left ear, Circle and Cross: Right and left ear air conduction hearing level respectively, Square bracket: Bone conduction hearing level, Triangle: both ears with intervention, Arrow: over measurement limit (B) There are no obvious differences between each ear in the cervical vestibular evoked myogenic potentials (right), and ocular vestibular evoked myogenic potentials (left).

Figure 3

(A) Pure-tone audiometry (PTA) shows bilateral progressive sensorineural hearing loss in the proband. After a cochlear implantation (CI) in the right ear, sound field hearing threshold tests with a CI show 40 dBSPL. Red: right ear, Blue: left ear, Circle and Cross: Right and left ear air conduction hearing level respectively, Square bracket: Bone conduction hearing level, Triangle: both ears with intervention, Arrow: over measurement limit (B) There are no obvious differences between each ear in the cervical vestibular evoked myogenic potentials (right), and ocular vestibular evoked myogenic potentials (left).