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There is robust evidence that sex (biological) and gender (behavioral/social) differences influence hearing loss risk and outcomes. These differences are noted for animals and humans—in the occurrence of hearing loss, hearing loss progression, and response to interventions. Nevertheless, many studies have not reported or disaggregated data by sex or gender. This article describes the influence of sex-linked biology (specifically sex-linked hormones) and gender on hearing and hearing interventions, including the role of sex-linked biology and gender in modifying the association between risk factors and hearing loss, and the effects of hearing loss on quality of life and functioning. Most prevalence studies indicate that hearing loss begins earlier and is more common and severe among men than women. Intrinsic sex-linked biological differences in the auditory system may account, in part, for the predominance of hearing loss in males. Sex- and gender-related differences in the effects of noise exposure or cardiovascular disease on the auditory system may help explain some of these differences in the prevalence of hearing loss. Further still, differences in hearing aid use and uptake, and the effects of hearing loss on health may also vary by sex and gender. Recognizing that sex-linked biology and gender are key determinants of hearing health, the present review concludes by emphasizing the importance of a well-developed research platform that proactively measures and assesses sex- and gender-related differences in hearing, including in understudied populations. Such research focus is necessary to advance the field of hearing science and benefit all members of society.

Current estimates suggest that nearly half a billion people worldwide are affected by hearing loss. Because of the major psychological, social, economic, and health ramifications, considerable efforts have been invested in identifying the genes and molecular pathways involved in hearing loss, whether genetic or environmental, to promote prevention, improve rehabilitation, and develop therapeutics. Genomic sequencing technologies have led to the discovery of genes associated with hearing loss. Studies of the transcriptome and epigenome of the inner ear have characterized key regulators and pathways involved in the development of the inner ear and have paved the way for their use in regenerative medicine. In parallel, the immense preclinical success of using viral vectors for gene delivery in animal models of hearing loss has motivated the industry to work on translating such approaches into the clinic. Here, we review the recent advances in the genomics of auditory function and dysfunction, from patient diagnostics to epigenetics and gene therapy.

The purpose of this manuscript is to provide pharmacists with education on hearing loss that colleagues in audiology believe is most critical for pharmacists. As well as highlighting insightful interventions pharmacists can make in collaboration with hearing professionals, such as audiologists, otolaryngologists, and otologists, to improve patient care. This project was initiated by professional students at the University of Maryland in both Baltimore and College Park campuses, after completing the interprofessional elective course IPE Care in Geriatrics. Upon completion of the course, the authors performed an extensive literature search and reviewed publications pertaining to pharmacy, audiology, and their integration.Hearing loss can have a significant impact on a patient’s quality of life. Older people are at an increased risk for experiencing hearing impairment, but often do not seek help from health care providers. Collaboration between audiologists, otolaryngologists, and pharmacists has the potential to improve patients’ access to hearing health and break barriers for patients. Important interventions that pharmacists can make to better serve their patients with hearing loss include screening, enhancing communication, and hearing aid assistance. This article also provides guidance on identifying patients who would be candidates for over-the-counter hearing aids and patients who should be referred to a hearing professional. This skill will become increasingly relevant with the emergence of over-the-counter hearing aids.

High-throughput cell type-specific multi-omic analyses have advanced our understanding of inner ear biology in an unprecedented way. The full benefit of these data, however, is reached from their re-use. Successful re-use of data requires identifying the natural users and ensuring proper data democratization and federation for their seamless and meaningful access. Here we discuss universal challenges in access and re-use of multi-omic data, possible solutions, and introduce the gEAR (the gene Expression Analysis Resource, umgear.org)—a tool for multi-omic data visualization, sharing and access for the ear field.

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org).

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org).KEY POINTSThe Neuroscience Multi-Omic Archive serves as the genomics data repository for the BRAIN Initiative.Genomic data from >50 million cells span all the major regions of the brains of humans and mice.We provide a searchable web portal, a cloud-computing interface, and a data visualization platform.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss. publishedVersion

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

Cochlear damage is often thought to result in hearing thresholds shift, whether permanent or temporary. The report of tinnitus in the absence of any clear deficit in cochlear function was believed to indicate that hearing loss and tinnitus, while comorbid, could arise independently from each other. In all likelihood, tinnitus that is not of central nervous system origin is associated with hearing loss. As a correlate, although a treatment of most forms of tinnitus will likely emerge in the years to come, curing tinnitus will first require curing hearing loss.

Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young-adult mice. Taking advantage of phenotypical differences in animals with similar genotypes, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior.

Mammalian hearing requires the development of the organ of Corti, a sensory epithelium comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we transcriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demonstrate the potential value and application of this data set., How the development of the cochlear epithelium is regulated is unclear. Here, the authors use single cell RNAseq analysis to provide insight into the transcriptional changes arising during development of the murine cochlear inner and outer hair cells.

During inner ear development, primary auditory neurons named spiral ganglion neurons (SGNs) are surrounded by otic mesenchyme cells, which express the transcription factor Pou3f4. Mutations in Pou3f4 are associated with DFNX2, the most common form of X-linked deafness and typically include developmental malformations of the middle ear and inner ear. It is known that interactions between Pou3f4-expressing mesenchyme cells and SGNs are important for proper axon bundling during development. However, Pou3f4 continues to be expressed through later phases of development, and potential interactions between Pou3f4 and SGNs during this period had not been explored. To address this, we documented Pou3f4 protein expression in the early postnatal mouse cochlea and compared SGNs in Pou3f4 knockout mice and littermate controls. In Pou3f4y/- mice, SGN density begins to decline by the end of the first postnatal week, with approximately 25% of SGNs ultimately lost. This period of SGN loss in Pou3f4y/- cochleae coincides with significant elevations in SGN apoptosis. Interestingly, this period also coincides with the presence of a transient population of Pou3f4-expressing cells around and within the spiral ganglion. To determine if Pou3f4 is normally required for SGN peripheral axon extension into the sensory domain, we used a genetic sparse labeling approach to track SGNs and found no differences compared with controls. We also found that Pou3f4 loss did not lead to changes in the proportions of Type I SGN subtypes. Overall, these data suggest that otic mesenchyme cells may play a role in maintaining SGN populations during the early postnatal period.

OBJECTIVES Cochlear implants (CIs) are considered a safe and effective intervention for more severe degrees of hearing loss in adults of all ages. Although older CI users ≥65 years of age can obtain large benefits in speech understanding from a CI, there is a growing body of literature suggesting that older CI users may not perform as well as younger CI users. One reason for this potential age-related limitation could be that default CI stimulation settings are not optimal for older CI users. The goal of this study was to determine whether improvements in speech understanding were possible when CI users were programmed with nondefault stimulation rates and to determine whether lower-than-default stimulation rates improved older CI users' speech understanding. DESIGN Sentence recognition was measured acutely using different stimulation rates in 37 CI users ranging in age from 22 to 87 years. Maps were created using rates of 500, 720, 900, and 1200 pulses per second (pps) for each subject. An additional map using a rate higher than 1200 pps was also created for individuals who used a higher rate in their clinical processors. Thus, the clinical rate of each subject was also tested, including non-default rates above 1200 pps for Cochlear users and higher rates consistent with the manufacturer defaults for subjects implanted with Advanced Bionics and Med-El devices. Speech understanding performance was evaluated at each stimulation rate using AzBio and Perceptually Robust English Sentence Test Open-set (PRESTO) sentence materials tested in quiet and in noise. RESULTS For Cochlear-brand users, speech understanding performance using non-default rates was slightly poorer when compared with the default rate (900 pps). However, this effect was offset somewhat by age, in which older subjects were able to maintain comparable performance using a 500-pps map compared with the default rate map when listening to the more difficult PRESTO sentence material. Advanced Bionics and Med-El users showed modest improvements in their overall performance using 720 pps compared with the default rate (>1200 pps). On the individual-subject level, 10 subjects (11 ears) showed a significant effect of stimulation rate, with 8 of those ears performing best with a lower-than-default rate. CONCLUSIONS Results suggest that default stimulation rates are likely sufficient for many CI users, but some CI users at any age can benefit from a lower-than-default rate. Future work that provides experience with novel rates in everyday life has the potential to identify more individuals whose performance could be improved with changes to stimulation rate.

Acoustic trauma is a feature of the industrial age, in general, and mechanized warfare, in particular. Noise-induced hearing loss (NIHL) and tinnitus have been the number 1 and number 2 disabilities at U.S. Veterans hospitals since 2006. In a reversal of original protocols to identify candidate genes associated with monogenic deafness disorders, unbiased genome-wide association studies now direct animal experiments in order to explore genetic variants common in Homo sapiens. However, even these approaches must utilize animal studies for validation of function and understanding of mechanisms. Animal research currently focuses on genetic expression profiles since the majority of variants occur in non-coding regions, implying regulatory divergences. Moving forward, it will be important in both human and animal research to define the phenotypes of hearing loss and tinnitus, as well as exposure parameters, in order to extricate genes related to acoustic trauma versus those related to aging. It has become clear that common disorders like acoustic trauma are influenced by large numbers of genes, each with small effects, which cumulatively lead to susceptibility to a disorder. A polygenic risk score, which aggregates these small effect sizes of multiple genes, may offer a more accurate description of risk for NIHL and/or tinnitus.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations., An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

We explored the transcriptional and epigenetic programs underlying the differentiation of hair cells from postnatal progenitor cells in cochlear organoids. Heterogeneity in the cells including cells with the transcriptional signatures of mature hair cells allowed a full picture of possible cell fates. Construction of trajectories identified Lgr5+ cells as progenitors for hair cells and the genomic data revealed gene regulatory networks leading to hair cells. We validated these networks, demonstrating dynamic changes both in expression and predicted binding sites of these transcription factors during organoid differentiation. We identified known regulators of hair cell development, Atoh1, Pou4f3, and Gfi1, and predicted novel regulatory factors, Tcf4, an E-protein and heterodimerization partner of Atoh1, and Ddit3, a CCAAT/enhancer-binding protein (C/EBP) that represses Hes1 and activates transcription of Wnt signaling-related genes. Deciphering the signals for hair cell regeneration from mammalian cochlear supporting cells reveals candidates for HC regeneration which is limited in the adult.

SUMMARY Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL., In brief Milon et al. show that cell-type-specific transcriptomic changes following noise exposure dominate the response compared to common changes. The noise-resilient type 1A neurons induce the ATF3/ATF4 stress-response pathway, and the outer hair cells and lateral wall downregulate mRNA metabolism genes and potassium transport genes, respectively., Graphical Abstract

Hearing loss is the most common form of sensory impairment in humans, with an anticipated rise in incidence as the result of recreational noise exposures. Hearing loss is also the second most common health issue afflicting military veterans. Currently, there are no approved therapeutics to treat sensorineural hearing loss in humans. While hearing loss affects both men and women, sexual dimorphism is documented with respect to peripheral and central auditory physiology, as well as susceptibility to age-related and noise-induced hearing loss. Physiological differences between the sexes are often hormone-driven, and an increasing body of literature demonstrates that the hormone estrogen and its related signaling pathways may in part, modulate the aforementioned differences in hearing. From a mechanistic perspective, understanding the underpinnings of the hormonal modulation of hearing may lead to the development of therapeutics for age related and noise induced hearing loss. Here the authors review a number of studies that range from human populations to animal models, which have begun to provide a framework for understanding the functional role of estrogen signaling in hearing, particularly in normal and aberrant peripheral auditory physiology.

Alström syndrome (OMIM #203800) is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early-onset type 2 diabetes mellitus (T2DM). To investigate the underlying mechanisms of T2DM phenotypes, we generated a loss-of-function deletion of alms1 in the zebrafish. We demonstrate conservation of hallmark clinical characteristics alongside metabolic syndrome phenotypes, including a propensity for obesity and fatty livers, hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1(−/−) mutants revealed changes consistent with insulin hypersecretion and glucose sensing failure, which were corroborated in cultured murine β-cells lacking Alms1. We also found evidence of defects in peripheral glucose uptake and concomitant hyperinsulinemia in the alms1(−/−) animals. We propose a model in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM associated with alms1 deficiency. These observations support the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes.

The gEAR portal (gene Expression Analysis Resource, umgear.org) is an open access community-driven tool for multi-omic and multi-species data visualization, analysis and sharing. The gEAR supports visualization of multiple RNA-seq data types (bulk, sorted, single cell/nucleus) and epigenomics data, from multiple species, time points and tissues in a single-page, user-friendly browsable format. An integrated scRNA-seq workbench provides access to raw data of scRNA-seq datasets for de novo analysis, as well as marker-gene and cluster comparisons of pre-assigned clusters. Users can upload, view, analyze and privately share their own data in the context of previously published datasets. Short, permanent URLs can be generated for dissemination of individual or collections of datasets in published manuscripts. While the gEAR is currently curated for auditory research with over 90 high-value datasets organized in thematic profiles, the gEAR also supports the BRAIN initiative (via nemoanalytics.org) and is easily adaptable for other research domains.

Objective The cellular diversity of the inner ear has presented a technical challenge in obtaining molecular insight into its development and function. The application of technological advancements in cell type-specific expression enable clinicians and researchers to leap forward from classic genetics to obtaining mechanistic understanding of congenital and acquired hearing loss. This understanding is essential for development of therapeutics to prevent and reverse diseases of the inner ear, including hearing loss. The objective of this study is to describe and compare the available tools for cell type-specific analysis of the ear, as a means to support decision making in study design. Study design Three major approaches for cell type-specific analysis of the ear including fluorescence-activated cell sorting (FACS), ribosomal and RNA pulldown techniques, and single cell RNA-seq (scRNA-seq) are compared and contrasted using both published and original data. Results We demonstrate the strength and weaknesses of these approaches leading to the inevitable conclusion that to maximize the utility of these approaches, it is important to match the experimental approach with the tissue of origin, cell type of interest, and the biological question. Often, a combined approach (eg, cell sorting and scRNA-seq or expression analysis using 2 separate approaches) is required. Finally, new tools for visualization and analysis of complex expression data, such as the gEAR platform (umgear.org), collate cell type-specific gene expression from the ear field and provide unprecedented access to both clinicians and researchers. Level of evidence N/A Laryngoscope, 2020.

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss:ATOH1(Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results demonstrate that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.