PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.

PKHD1L1, A Gene Involved in the Stereocilia Coat, Causes Autosomal Recessive Nonsyndromic Hearing Loss.

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modelling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modelling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.

Otolaryngologic Manifestations of Trisomy 13 and Trisomy 18 in Pediatric Patients.

OBJECTIVE: The survival rate of patients with trisomy 13 and trisomy 18 has increased dramatically over the past two decades. We sought to comprehensively describe the otolaryngologic clinical characteristics and procedures required for these patients at our institution. METHODS: We performed algorithmic identification of patients with a diagnosis of trisomy 13 and trisomy 18 for whom the otolaryngology service provided inpatient or outpatient care at our institution between the dates of February 1997 and March 2021. RESULTS: Of the 47 patients studied, 18 patients had a diagnosis of trisomy 13, and 29 had a diagnosis of trisomy 18. Complete trisomy was present in 44% (8/18) of trisomy 13 patients and 55% (16/29) of trisomy 18 patients. 81% of patients were living at the time of the study. About 94% (44/47) of patients required consultation with another specialty in addition to Otolaryngology. Overall, the most common diagnoses among this cohort were gastroesophageal reflux disease (47%), dysphagia (40%), otitis media (38%), and obstructive sleep apnea (34%). Nearly three-quarters (74%) of patients studied required an otolaryngologic procedure. The most common surgical procedure was tonsillectomy and/or adenoidectomy. Patients with trisomy 18 were significantly more likely to have external auditory canal stenosis and obstructive sleep apnea whereas patients with trisomy 13 were more likely to have cleft lip and palate. CONCLUSIONS: Patients with a diagnosis of trisomy 13 or 18 often require multidisciplinary management and the range of required care spans the breadth of otolaryngology. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1501-1506, 2023.

Programming Levels and Speech Perception in Pediatric Cochlear Implant Recipients With Enlarged Vestibular Aqueduct or GJB2 Mutation.

OBJECTIVE: To determine the relationship between hearing loss etiology, cochlear implant (CI) programming levels, and speech perception performance in a large clinical cohort of pediatric CI recipients. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospitals. PATIENTS: A total of 136 pediatric CI recipients (218 ears) were included in this study. All patients had diagnoses of either enlarged vestibular aqueduct (EVA) or GJB2 (Connexin-26) mutation confirmed via radiographic data and/or genetic reports. All patients received audiologic care at either Boston Children's Hospital or Massachusetts Eye and Ear in Boston, MA, between the years 1999 and 2020. MAIN OUTCOME MEASURES: Electrode impedances and programming levels for each active electrode and speech perception scores were evaluated as a function of etiology (EVA or GJB2 mutation). RESULTS: Children with EVA had significantly higher impedances and programming levels (thresholds and upper stimulation levels) than the children with GJB2 mutation. Speech perception scores did not differ as a function of etiology in this sample; rather, they were positively correlated with duration of CI experience (time since implantation). CONCLUSIONS: Differences in electrode impedances and CI programming levels suggest that the electrode-neuron interface varies systematically as a function of hearing loss etiology in pediatric CI recipients with EVA and those with GJB2 mutation. Time with the CI was a better predictor of speech perception scores than etiology, suggesting that children can adapt to CI stimulation with experience.

Genetic testing for pediatric hearing loss: no time to waste.

Since the discovery of the first human deafness gene a quarter of a century ago, our approach to clinical evaluation of children with hearing loss has changed dramatically. What was once a low-yield scattershot approach has changed to a clearly definable pathway involving genetic testing, imaging, and congenital cytomegalovirus testing. There still however is a great deal of work to be done to expand the correct use of this testing, particularly genetic testing.

Hearing Aid Use in Children With Unilateral Hearing Loss: A Randomized Crossover Clinical Trial.

OBJECTIVES/HYPOTHESIS: In children with mild to moderately severe unilateral hearing loss (UHL), assess whether subject-reported quality of life (QOL) and teacher- and parent-reported perception of listening difficulty are affected by use of a hearing aid (HA) with baseline accommodations, compared to children receiving only baseline accommodations. STUDY DESIGN: Randomized crossover clinical trial. METHODS: Thirty-seven children 6-12 years of age with mild to moderately severe UHL and ≥80% word recognition scores in the poorer hearing ear were randomized into arm 1, using baseline accommodations (frequency-modulated system and strategic seating) for 12 weeks, followed by addition of a HA for 12 weeks. The other participants were randomized into the reverse methodology: arm 2, using a HA in addition to baseline accommodations for 12 weeks, followed by baseline accommodations alone. Surveys of QOL (Hearing Environments and Reflection on Quality of Life) and listening difficulties or challenges with hearing amplification (CHILD and LIFE-R questionnaires) were administered at 6-week intervals. Differences in mean survey scores, percent change, and improvement over time were computed between the two arms and inter-arm intervals. Per-protocol analysis was used. RESULTS: Of the 37 children enrolled, 34 children underwent the study interventions and were included in the analysis, (arm 1 = 20, arm 2 = 14) (mean [standard deviation] age = 8 [1.5] years; 21 boys [61.8%]). Survey scores averaged across both arms during the HA interval (77.79 [15.13]) were significantly higher than during the baseline-only interval (69.67 [14.69], P = .036). There was no significant difference between trial arms in mean scores between the two HA intervals (P = .450) and two baseline-only intervals (P = .539). CONCLUSIONS: Hearing-related QOL and listening ability improved in children who met eligibility criteria with mild to moderately severe UHL with HA use compared with baseline accommodations alone. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02269124. LEVEL OF EVIDENCE: 1 Laryngoscope, 132:881-888, 2022.

Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings.

Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% of diagnosed cases. While large deletions involving the gene STRC are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss.

Neuroimaging in Kabuki syndrome and another KMT2D-related disorder.

Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.

A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing.

Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.

Incidence, Time Course, and Implications of Electrode Abnormalities in Pediatric Cochlear Implant Recipients.

OBJECTIVES: To identify the incidence of specific abnormal impedance patterns or electrode faults, and determine their implication and significance, in a pediatric population of cochlear implant recipients. DESIGN: Nine hundred fifty-six cochlear implant devices (621 recipients) were included in this retrospective study. Devices were included if the implantation surgery was performed at our tertiary care hospital, and the recipient was 21 years of age or younger at the time the device was implanted. Device models incapable of producing impedance measures by telemetry were excluded from the study. Individual devices with abnormal impedance measures indicating an open circuit (OC), short circuit (SC), or partial short circuit (partial SC) were included in the study, unless these abnormalities occurred only in the OR and not postoperatively. Device and patient characteristics were examined to determine their relationship to increased incidence of electrode faults or atypical patterns. RESULTS: The incidence of software-identified electrode faults in our exclusively pediatric population was similar to that reported in the literature containing mixed-age cohorts. Nine percent of devices experienced at least one OC or one pair of SCs. Although higher incidence of these faults was seen in some specific device models, the long-term average of these faults was equivalent across manufacturers. No factors examined in this study increased the likelihood of experiencing a software-identified electrode fault. Within the study period under examination (October 1997 to March 2018), partial SCs (presenting as zig-zag or low-flat impedance patterns) were only observed in Cochlear devices. While the incidence of these partial SC abnormalities (non-software-identified faults) was 6% across all models of Cochlear devices, the CI24RCS experienced the highest incidence of partial SCs. The incidence of this pattern was lower in models manufactured after CI24RCS. CONCLUSIONS: This study provides incidence of various cochlear implant electrode impedance abnormalities across a large cohort of pediatric recipients. The incidence of all electrode abnormalities was relatively low, particularly partial SCs, which are less well recognized and not currently identified by clinician-accessible software. Incidence of software-identified electrode faults (i.e., SCs and OCs) in our pediatric-only study is similar to the incidence reported in other mixed-population and adult-only studies. These common electrode faults generally are not associated with device failure, and clinicians should feel comfortable reassuring families that an individual electrode fault does not imply an impending device failure. Conversely, those atypical impedance patterns not currently flagged by the programming software as abnormal, but visible to the clinician's eye (i.e., partial SCs in zig-zag or low-flat patterns), have a higher likelihood of device damage and failure. Performance in patients with electrode arrays exhibiting these atypical patterns should be closely monitored for any functional decrement, and proactively managed to maintain performance whenever possible.

Validation of a Parent Proxy Quality-of-Life Measure for Young Children With Hearing Loss.

OBJECTIVES: No hearing-related quality of life (QL) questionnaire currently exists for children < 7 years. This study aimed to develop and evaluate the construct validity and reliability of a new parent-proxy Preschool Hearing Environments and Reflection on Quality of Life (HEAR-QL) questionnaire. METHODS: Parents of children 2 to 6 years old with any hearing loss (HL) were recruited from multiple sites. To evaluate the new measure's construct validity, participants completed a 70-item preschool HEAR-QL and validated questionnaires measuring hearing and communication functioning (Parents' Evaluation of Aural/Oral Performance of Children), generic pediatric QL (Pediatric Quality of Life Inventory Parent Report, PedsQL), family functioning (PedsQL Family Impact Module), and parent well-being (Patient Reported Outcomes Measurement Information System Adult Global Report). Participants completed the preschool HEAR-QL 2 weeks later to measure test-retest reliability. Exploratory principal components analysis was used to reduce the number of items and determine the underlying HEAR-QL factor structure. Analysis of variance examined HEAR-QL differences by HL. RESULTS: Among 205 parents, 144 had children with bilateral HL, 50 had children with unilateral HL, 10 had children with normal hearing (NH), and one child's hearing status was unspecified. The 70-item questionnaire was reduced to 23 items with five underlying factors: Behavior and Attention, Hearing Environments, New Social Situations, Social Interactions, and Communication. Cronbach's alpha for each factor ranged from 0.80 to 0.91. Test-retest reliability was 0.93. Moderate-to-strong correlations (r > .300) were observed between each Preschool HEAR-QL factor and previously validated measures. Hearing Environments scores differed significantly between children with NH and any HL. CONCLUSION: Preschool HEAR-QL correlations with other measures supported its construct validity. Discriminant validity testing requires a larger sample of children with NH. LEVEL OF EVIDENCE: NA Laryngoscope, 131:663-670, 2021.

Genomic diversity of bacteriophages infecting Microbacterium spp.

The bacteriophage population is vast, dynamic, old, and genetically diverse. The genomics of phages that infect bacterial hosts in the phylum Actinobacteria show them to not only be diverse but also pervasively mosaic, and replete with genes of unknown function. To further explore this broad group of bacteriophages, we describe here the isolation and genomic characterization of 116 phages that infect Microbacterium spp. Most of the phages are lytic, and can be grouped into twelve clusters according to their overall relatedness; seven of the phages are singletons with no close relatives. Genome sizes vary from 17.3 kbp to 97.7 kbp, and their G+C% content ranges from 51.4% to 71.4%, compared to ~67% for their Microbacterium hosts. The phages were isolated on five different Microbacterium species, but typically do not efficiently infect strains beyond the one on which they were isolated. These Microbacterium phages contain many novel features, including very large viral genes (13.5 kbp) and unusual fusions of structural proteins, including a fusion of VIP2 toxin and a MuF-like protein into a single gene. These phages and their genetic components such as integration systems, recombineering tools, and phage-mediated delivery systems, will be useful resources for advancing Microbacterium genetics.

Genetics of pediatric hearing loss: A functional perspective.

OBJECTIVES: This article reviews the current role of genetics in pediatric hearing loss (HL). METHODS: A review of the current literature regarding the genetic basis of HL in children was performed. RESULTS: To date, 119 nonsyndromic genes have been associated with HL. There are also hundreds of syndromic causes that have HL as part of the clinical phenotype. CONCLUSIONS: Identifying HL genes coupled with clinical characteristics ("genotype-phenotype") yields a more accurate diagnosis and prognosis. Although the complexity of the auditory apparatus presents challenges, gene therapy is emerging and may be a viable management option in the future.

Association of Blood Type With Postsurgical Mucosal Bleeding in Pediatric Patients Undergoing Tonsillectomy With or Without Adenoidectomy.

Importance: Blood type (BT) O has been identified as a risk factor for bleeding complications, while non-O BTs may increase risk for thromboembolic events. Limited data are available in children undergoing tonsillectomy with or without adenoidectomy. Objective: To determine whether BT O is associated with hemorrhage after tonsillectomy with or without adenoidectomy. Design, Setting, and Participants: Retrospective cohort study of patients younger than 22 years who underwent tonsillectomy with or without adenoidectomy at a single institution between January 1, 2008, and August 7, 2017. Statistical analysis was performed from November 2017 to January 2019. Main Outcomes and Measures: Prevalence of hemorrhage following surgery was defined as any bleeding requiring cauterization up to 1 month after the procedure. Data on sex, age, von Willebrand disease (VWD) status, BT, white blood cell counts, and platelet counts closest to date of surgery were collected from an electronic medical record system, and the association of these factors with hemorrhage following surgery was investigated. Results: A total of 14 951 pediatric patients (median [range] age, 5.6 [0.8-21.9] years; 6956 [46.5%] female) underwent tonsillectomy with or without adenoidectomy. Prevalence of hemorrhage following the procedure was 3.9% (578 patients) for the full cohort and 2.8% (362 of 13 065) for patients with no BT identified or preprocedure VWD panel results at baseline. Children who had a BT identified and/or a VWD panel before surgery had higher bleeding rates (BT only, 14.9% [172 of 1156]; preprocedure VWD panel only, 4.6% [28 of 607]; and BT and preprocedure VWD panel, 13.0% [16 of 123]), all of which were significantly different from the baseline bleeding rate (P < .001). While the bleeding rates in children with BT O were not statistically different from those with non-O BT (14.8% and 14.6%, respectively; P > .99), mean von Willebrand factor values were statistically different (mean [SD] von Willebrand factor antigen level in O group, 86.9 [42.4] IU/dL in the O group vs 118.0 [53.8] IU/dL in the non-O group; P = .002; and mean [SD] von Willebrand factor ristocetin-cofactor in the O group, 72.2 [44.3] IU/dL vs 112.6 [68.0] IU/dL in the non-O group; P = .001). In addition, children older than 12 years had increased bleeding rates in the full cohort (8.3% vs 3.2%), in the testing-naive cohort (6.5% vs 2.3%), and in those with a preprocedure VWD panel only (13.5% vs 3.1%) compared with children aged 12 years or younger. Conclusions and Relevance: Type O blood was not a risk factor associated with hemorrhage after tonsillectomy with or without adenoidectomy despite lower baseline von Willebrand factor antigen and von Willebrand factor ristocetin-cofactor values in children with BT O vs those with non-O BT in our study cohort. No association was found between VWD status and bleeding, and there was no difference in VWD panel values in those who experienced hemorrhage vs those who did not within BT groups. Further studies elucidating the utility of von Willebrand factor values for children undergoing tonsillectomy with or without adenoidectomy are needed.

Preclinical testing of AAV9-PHP.B for transgene expression in the non-human primate cochlea.

In a number of mouse models of hereditary deafness, therapeutic transgene delivery to the cochlea and vestibular organs using adeno-associated viral vectors (AAVs) has shown striking rescue of hearing and balance. However, only a subset of AAV capsids have shown efficacy in transducing both inner hair cells and outer hair cells, and it is also not clear which of these can be translated to treatment of human inner ear. We recently reported efficient transgene expression of a GFP reporter in a non-human primate cochlea, in both inner and outer hair cells, following injection of the AAV9 capsid variant PHP.B via the round window membrane (RWM). However efficiency was poor at a lower dose. To further define the transduction potential of AAV9-PHP.B, we have performed a dosing study in the cynomolgus monkey and assessed vector-encoded GFP expression. Three animals were injected in both ears and four doses were tested. We describe a transmastoid surgical approach needed to access the RWM of this common primate model. We found that AAV9-PHP.B transduced nearly 100% of both IHCs and OHCs, from base to apex, at the higher doses (3.5 × 1011 and 7 × 1011 vector genomes). However, at lower doses there was a steep reduction in viral transduction. Thus, AAV9-PHP.B efficiently transduces the IHCs and OHCs of nonhuman primates, and should be considered as an AAV capsid for inner ear gene therapy in humans.

Genome Sequences of Six Cluster N Mycobacteriophages, Kevin1, Nenae, Parmesanjohn, ShrimpFriedEgg, Smurph, and SpongeBob, Isolated on Mycobacterium smegmatis mc2155.

The annotation of six cluster N Mycobacterium smegmatis phages (Kevin1, Nenae, Parmesanjohn, ShrimpFriedEgg, Smurph, and SpongeBob) reveals regions of genomic diversity, particularly within the central region of the genome. The genome of Kevin1 includes two orphams (genes with no similarity to other phage genes), with one predicted to encode an AAA-ATPase.

A novel missense mutation in TFAP2B associated with Char syndrome and central diabetes insipidus.

Char syndrome is characterized by persistent patent ductus arteriosus (PDA) associated with hand-skeletal abnormalities and distinctive facial dysmorphism. Pathogenic variants in the transcription factor gene TFAP2B have been shown to cause Char syndrome; however, there is significant phenotypic variability linked to variant location. Here, we report a pediatric patient with a novel de novo variant in the fifth exon of TFAP2B, c.917C > T (p.Thr306Met), who presented with PDA, patent foramen ovale, postaxial polydactyly of the left fifth toe and clinodactyly of the left fourth toe, sensorineural hearing loss, scoliosis, dental anomalies, and central diabetes insipidus (CDI). CDI, scoliosis, and hearing loss have not previously been reported in a patient with Char syndrome, and while the association may be coincidental, this report expands the genotypes and potentially phenotypes associated with this syndrome.

Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate.

Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector.

Validation of a portable hearing assessment tool: Agilis Health Mobile Audiogram.

OBJECTIVES: To examine if the tablet-based Agilis Health Mobile Audiogram (Agilis Audiogram) is an effective and valid measure of hearing thresholds compared to a pure-tone audiogram in an adult and pediatric population. METHODS: Participants underwent an otologic exam, conventional audiometric evaluation and the self-administered Agilis Audiogram. We examined whether the difference of pure-tone average (PTA) between the two measurement techniques fell within the equivalence range of ±8 dB. The Agilis Audiogram was administered twice for each subject to assess test-retest reliability of the application. RESULTS: A total of 54 ears from 27 participants were evaluated. The average time to complete the self-administered Agilis Audiogram was 10 min. Among participants with normal hearing, the average PTA from conventional audiometric evaluation was 8.9 dB (±3.8) and the average PTA from the Agilis Audiogram was 8.5 dB (±4.5), with mean difference of 0.4 dB (±4.2; 95% CI -1.0 to 1.7 dB) falling within the equivalence range (-8 to 8 dB). Among participants with confirmed hearing loss, the average PTA was 22.5 dB (±17.1) from conventional audiometric evaluation and 24.3 dB (±16.6) from the Agilis Audiogram, with mean difference of -1.8 dB (±5.4; 95% CI -4.9 to 1.3 dB), falling within the equivalence range. Overall, there was a significant correlation between conventional audiometric evaluation and the Agilis Audiogram (Pearson correlation = 0.93; p < 0.001). CONCLUSION: Thresholds obtained by the Agilis Audiogram were found to be a valid measure of hearing among adults with normal hearing and children with hearing loss in the mild-moderate range.