Autosomal Recessive Hereditary Hearing Loss Research Articles

Combined AAV-mediated gene replacement therapy improves auditory function in a mouse model of human DFNB42 deafness

Hearing loss is a common disorder affecting nearly 20% of the world's population. Recently, studies have shown that inner ear gene therapy can improve auditory function in several mouse models of hereditary hearing loss. In most of these studies, the underlying mutations affect only a small number of cell types of the inner ear (e.g., sensory hair cells). Here, we applied inner ear gene therapy to the Ildr1Gt(D178D03)Wrst (Ildr1w-/-) mouse, a model of human DFNB42, non-syndromic autosomal recessive hereditary hearing loss associated with ILDR1 variants. ILDR1 is an integral protein of the tricellular tight junction complex and is expressed by diverse inner ear cell types in the organ of Corti and the cochlear lateral wall. We simultaneously applied two synthetic adeno-associated viruses (AAVs) with different tropism to deliver Ildr1 cDNA to the Ildr1w-/- mouse inner ear: one targeting the organ of Corti (AAV2.7m8) and the other targeting the cochlear lateral wall (AAV8BP2). We showed that combined AAV2.7m8/AAV8BP2 gene therapy improves cochlear structural integrity and auditory function in Ildr1w-/- mice.

Phenotype-genotype analysis of the autosomal recessive hereditary hearing loss caused by OTOA variations

Objective: To analyze the phenotypic-genotypic characteristics of hereditary deafness caused by OTOA gene variations. Methods: Family histories, clinical phenotypes and gene variations of six pedigrees were analyzed, which were diagnosed with hearing loss caused by OTOA gene variations at the PLA General Hospital from September 2015 to January 2022. The sequence variations were verified by Sanger sequencing and the copy number variations were validated by multiplex ligation-dependent probe amplification (MLPA) in the family members. Results: The hearing loss phenotype caused by OTOA variations ranged from mild to moderate in the low frequencies, and from moderate to severe in the high frequencies in the probands, which came from six sporadic pedigrees, among which a proband was diagnosed as congenital deafness and five were diagnosed as postlingual deafness. One proband carried homozygous variations and five probands carried compound heterozygous variations in OTOA gene. Nine pathogenic variations (six copy number variations, two deletion variations and one missense variation) and two variations with uncertain significance in OTOA were identified in total, including six copy number variations and five single nucleotide variants, and three of the five single nucleotide variants were firstly reported [c.1265G>T(p.Gly422Val),c.1534delG(p.Ala513Leufs*11) and c.3292C>T(p.Gln1098fs*)]. Conclusions: OTOA gene variations can lead to autosomal recessive nonsyndromic hearing loss. In this study, the hearing loss caused by OTOA defects mostly presents as bilateral, symmetrical, and postlingual, and that of a few presents as congenital. The pathogenic variations of OTOA gene are mainly copy number variations followed by deletion variations and missense variations.

A New Pathogenic Variant in the TRIOBP Associated with Profound Deafness Is Remediable with Cochlear Implantation

Background and Objectives: A rare type of nonsyndromic autosomal recessive hereditary hearing loss is caused by pathogenic mutations in the TRIOBP gene mostly involving exons 6 and 7. These mutations cause hearing loss originating from dysfunction of sensory inner ear hair cells. Of all the affected siblings, 2 brothers and 1 sister, part of an Afghan family, were referred to our clinic for diagnostic workup and candidacy selection for cochlear implantation (CI). Methods: Molecular analysis showed a homozygous c.1342C > T p. (Arg448*) pathogenic variant in exon 7 of the TRIOBP gene (reference sequence NM_001039141.2) in all 3 affected siblings. Clinical audiometry demonstrated profound sensorineural hearing loss in all 3 affected siblings (2 males and 1 female), and they were implanted unilaterally. Results: One month after activation, the pure-tone averages with the CI processor were between 30 and 23 dBHL. Ten months after the first activation of the implant, open-set speech audiometry test could be performed for the first time in the 2 younger CI recipients (S5 and S9), and they could identify up to a maximum 77% phonemes correctly. The oldest brother (S12) could not yet perform open-set speech audiometry at that moment. Conclusions: Implant outcomes are better with normal inner ear anatomy in general. The earlier congenital patients are implanted, the better their outcomes. Here, we demonstrate both statements are true in a homozygous c.1342C > T p. (Arg448*) pathogenic variant in the TRIOBP gene in all 3 affected siblings.

Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families

Hereditary hearing loss is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

BackgroundCountries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous,...

A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR‐based approach and next generation sequencing

Implementing DNA diagnostics in clinical practice for extremely heterogeneous diseases such as hearing loss is challenging, especially when attempting to reach high sensitivity and specificity in a cost-effective fashion. Next generation sequencing has enabled the development of such a test, but the most commonly used genomic target enrichment methods such as hybridization-based capture suffer from restrictions. In this study, we have adopted a new flexible approach using microdroplet PCR-based technology for target enrichment, in combination with massive parallel sequencing to develop a DNA diagnostic test for autosomal recessive hereditary hearing loss. This approach enabled us to identify the genetic basis of hearing loss in 9 of 24 patients, a success rate of 37.5%. Our method also proved to have high sensitivity and specificity. Currently, routine molecular genetic diagnostic testing for deafness is in most cases only performed for the GJB2 gene and a positive result is typically only obtained in 10-20% of deaf children. Individuals with mutations in GJB2 had already been excluded in our selected set of 24 patients. Therefore, we anticipate that our deafness test may lead to a genetic diagnosis in roughly 50% of unscreened autosomal recessive deafness cases. We propose that this diagnostic testing approach represents a significant improvement in clinical practice as a standard diagnostic tool for children with hearing loss.

The genetic load for hereditary hearing impairment in Chinese population and its clinical implication

ObjectiveTo understand the genetic load in the Chinese population for improvement in diagnosis, prevention and rehabilitation of deafness. MethodsDNA samples, immortalized cell lines as well as detailed clinical and audiometric data were collected through a national genetic resources collecting network. Two conventional genetic approaches were used in the studies. Linkage analysis in X chromosome and autosomes with microsatellite markers were performed in large families for gene mapping and positional cloning of novel genes. Candidate gene approach was used for screening themtDNA 12SrRNA, GJB2andSLC26A4mutations in population–based samples. ResultsA total of 2, 572 Chinese hearing loss families or sporadic cases were characterized in the reported studies, including seven X–linked, one Y–linked, 28 large and multiplex autosomal dominant hearing loss families, 607 simplex autosomal recessive hereditary hearing loss families, 100 mitochondrial inheritance families, 147GJB2induced hearing loss cases, 230 cases with enlarged vestibular aqueduct (EVA) syndrome, 169 sporadic cases with auditory neuropathy, and 1, 283 sporadic sensorineural hearing loss cases. Through linkage analysis or sequence analysis, two X–linked families were found transmitting two novel mutations in thePOU3F4gene, while another X–linked family was mapped onto a novel locus, nominated asAUNX1(auditory neuropathy, X–linked locus 1). The only Y–linked family was mapped onto theDFNY1locus (Y–linked locus 1,DFNY1). Eight of the 28 autosomal dominant families were linked to various autosomal loci. In population genetics studies, 2, 567 familial cases and sporadic patients were subjected to mutation screening for three common hearing loss genes:mtDNA 12S rRNA 1555G, GJB2andSLC26A4.The auditory neuropathy cases in our samples were screened forOTOFgene mutations. ConclusionsThese data show that the Chinese population has a genetic load on hereditary hearing loss. Establishing personalized surveillance and prevention models for hearing loss based on genetic research will provide the opportunity to decrease the prevalence of deafness in the Chinese population.