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Hearing Disorders: HELP
Articles by Richard J. H. Smith
Based on 77 articles published since 2009
(Why 77 articles?)
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Between 2009 and 2019, R. Smith wrote the following 77 articles about Hearing Disorders.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Hearing loss in the pediatric patient. 2016

Liming, Bryan J / Carter, John / Cheng, Alan / Choo, Daniel / Curotta, John / Carvalho, Daniela / Germiller, John A / Hone, Stephen / Kenna, Margaret A / Loundon, Natalie / Preciado, Diego / Schilder, Anne / Reilly, Brian J / Roman, Stephane / Strychowsky, Julie / Triglia, Jean-Michel / Young, Nancy / Smith, Richard J H. ·Department of Otolaryngology -Head and Neck Surgery, University of Iowa Health Care, Iowa City, IA, USA. Electronic address: Bryan-liming@uiowa.edu. · Department of Otolaryngology- Head and Neck Surgery, Ochsner Medical Center, New Orleans, LA, USA. · Sydney Children's Hospital Network, Sydney, Australia. · Cincinnati Children's Hospital, Cincinnati, OH, USA. · Rady Children's Hospital, San Diego, CA, USA. · Children's Hospital of Philadelphia, Philadelphia PA, USA. · Our Lady's Children's Hospital, Crumlin, Dublin, Ireland. · Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston MA, USA. · Pediatric ENT Department, Hopital Necker-Enfants Malades, AP-HP Universite Paris Descartes, Paris, France. · Department of Otolaryngology, Children's National Hospital, Washington DC, USA. · Evident, UCL Ear Institute, Royal National Throat, Nose and Ear Hospital, London UK. · Department of Pediatric Otolaryngology, La Timone Children's Hospital, Aix-Marseille Universite', Marseille, France. · Paediatric Otolaryngology-Head and Neck Surgery-Children's Hospital at London Health Sciences Centre, London, Ontario, Canada. · Division of Otolaryngology-Head and Neck Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago IL, USA. · Department of Otolaryngology -Head and Neck Surgery, University of Iowa Health Care, Iowa City, IA, USA. ·Int J Pediatr Otorhinolaryngol · Pubmed #27729144.

ABSTRACT: OBJECTIVE: To provide recommendations for the workup of hearing loss in the pediatric patient. METHODS: Expert opinion by the members of the International Pediatric Otolaryngology Group. RESULTS: Consensus recommendations include initial screening and diagnosis as well as the workup of sensorineural, conductive and mixed hearing loss in children. The consensus statement discusses the role of genetic testing and imaging and provides algorithms to guide the workup of children with hearing loss. CONCLUSION: The workup of children with hearing loss can be guided by the recommendations provided herein.

2 Review Congenital hearing loss. 2017

Korver, Anna M H / Smith, Richard J H / Van Camp, Guy / Schleiss, Mark R / Bitner-Glindzicz, Maria A K / Lustig, Lawrence R / Usami, Shin-Ichi / Boudewyns, An N. ·Department of Pediatrics, St Antonius Hospital, PO BOX 2500, 3430 EM Nieuwegein, The Netherlands. · Molecular Otolaryngology and Renal Research Laboratories and the Genetics PhD Program, University of Iowa, Iowa City, Iowa, USA. · Department of Medical Genetics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium. · Division of Pediatric Infectious Diseases and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA. · Genetics and Genomic Medicine Programme, University College London Great Ormond Street Institute of Child Health, London, UK. · Department of Otolaryngology-Head and Neck Surgery, Columbia University Medical Center, New York, New York, USA. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Head and Neck Surgery, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium. ·Nat Rev Dis Primers · Pubmed #28079113.

ABSTRACT: Congenital hearing loss (hearing loss that is present at birth) is one of the most prevalent chronic conditions in children. In the majority of developed countries, neonatal hearing screening programmes enable early detection; early intervention will prevent delays in speech and language development and has long-lasting beneficial effects on social and emotional development and quality of life. A diagnosis of hearing loss is usually followed by a search for an underlying aetiology. Congenital hearing loss might be attributed to environmental and prenatal factors, which prevail in low-income settings; congenital infections, particularly cytomegalovirus infection, are also a common risk factor for hearing loss. Genetic causes probably account for the majority of cases in developed countries; mutations can affect any component of the hearing pathway, in particular, inner ear homeostasis (endolymph production and maintenance) and mechano-electrical transduction (the conversion of a mechanical stimulus into electrochemical activity). Once the underlying cause of hearing loss is established, it might direct therapeutic decision making and guide prevention and (genetic) counselling. Management options include specific antimicrobial therapies, surgical treatment of craniofacial abnormalities and implantable or non-implantable hearing devices. An improved understanding of the pathophysiology and molecular mechanisms that underlie hearing loss and increased awareness of recent advances in genetic testing will promote the development of new treatment and screening strategies.

3 Review Heterogeneity of Hereditary Hearing Loss in Iran: a Comprehensive Review. 2016

Beheshtian, Maryam / Babanejad, Mojgan / Azaiez, Hela / Bazazzadegan, Niloofar / Kolbe, Diana / Sloan-Heggen, Christina / Arzhangi, Sanaz / Booth, Kevin / Mohseni, Marzieh / Frees, Kathy / Azizi, Mohammad Hossein / Daneshi, Ahmad / Farhadi, Mohammad / Kahrizi, Kimia / Smith, Richard Jh / Najmabadi, Hossein. ·Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. · Department of Otolaryngology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. · Academy of Medical Sciences Islamic Republic of Iran, Tehran, Iran. · Head and Neck Surgery Department and Research Center, Iran University of Medical Sciences, Tehran, Iran. ·Arch Iran Med · Pubmed #27743438.

ABSTRACT: A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment.

4 Review Navigating genetic diagnostics in patients with hearing loss. 2016

Sloan-Heggen, Christina M / Smith, Richard J H. ·aMolecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa bDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine cInterdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, USA. ·Curr Opin Pediatr · Pubmed #27552069.

ABSTRACT: PURPOSE OF REVIEW: In the age of targeted genomic enrichment and massively parallel sequencing, there is no more efficient genetic testing method for the diagnosis of hereditary hearing loss. More clinical tests are on the market, which can make choosing good tests difficult. RECENT FINDINGS: More and larger comprehensive genetic studies in patients with hearing loss have been published recently. They remind us of the importance of looking for both single nucleotide variation and copy number variation in all genes implicated in nonsyndromic hearing loss. They also inform us of how a patient's history and phenotype provide essential information in the interpretation of genetic data. SUMMARY: Choosing the most comprehensive genetic test improves the chances of a genetic diagnosis and thereby impacts clinical care.

5 Review Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. 2015

Shearer, A Eliot / Smith, Richard J H. ·Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. · Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa College of Medicine, Iowa City, Iowa, USA richard-smith@uiowa.edu. ·Otolaryngol Head Neck Surg · Pubmed #26084827.

ABSTRACT: OBJECTIVE: To evaluate the use of new genetic sequencing techniques for comprehensive genetic testing for hearing loss. DATA SOURCES: Articles were identified from PubMed and Google Scholar databases using pertinent search terms. REVIEW METHODS: Literature search identified 30 studies as candidates that met search criteria. Three studies were excluded, and 8 studies were found to be case reports. Twenty studies were included for review analysis, including 7 studies that evaluated controls and 16 studies that evaluated patients with unknown causes of hearing loss; 3 studies evaluated both controls and patients. CONCLUSIONS: In the 20 studies included in the review analysis, 426 control samples and 603 patients with unknown causes of hearing loss underwent comprehensive genetic diagnosis for hearing loss using massively parallel sequencing. Control analysis showed a sensitivity and specificity >99%, sufficient for clinical use of these tests. The overall diagnostic rate was 41% (range, 10%-83%) and varied based on several factors, including inheritance and prescreening prior to comprehensive testing. There were significant differences in platforms available with regard to the number and type of genes included and whether copy number variations were examined. Based on these results, comprehensive genetic testing should form the cornerstone of a tiered approach to clinical evaluation of patients with hearing loss along with history, physical examination, and audiometry and can determine further testing that may be required, if any. IMPLICATIONS FOR PRACTICE: Comprehensive genetic testing has become the new standard of care for genetic testing for patients with sensorineural hearing loss.

6 Review Genetics: advances in genetic testing for deafness. 2012

Shearer, A Eliot / Smith, Richard J H. ·Department of Otolaryngology - Head & Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. ·Curr Opin Pediatr · Pubmed #23042251.

ABSTRACT: PURPOSE OF REVIEW: To provide an update on recently discovered human deafness genes and to describe advances in comprehensive genetic testing platforms for deafness, both of which have been enabled by new massively parallel sequencing technologies. RECENT FINDINGS: Over the review period, three syndromic and six nonsyndromic deafness genes have been discovered, bringing the total number of nonsyndromic deafness genes to 64. Four studies have shown the utility of massively parallel sequencing for comprehensive genetic testing for deafness. Three of these platforms have been released on a clinical or commercial basis. SUMMARY: Deafness is the most common sensory deficit in humans. Genetic diagnosis has traditionally been difficult due to extreme genetic heterogeneity and a lack of phenotypic variability. For these reasons, comprehensive genetic screening platforms have been developed with the use of massively parallel sequencing. These technologies are also accelerating the pace of gene discovery for deafness. Because genetic diagnosis is the basis for molecular therapies, these advances lay the foundation for the clinical care of deaf and hard-of-hearing persons in the future.

7 Review Deafness in the genomics era. 2011

Shearer, A Eliot / Hildebrand, Michael S / Sloan, Christina M / Smith, Richard J H. ·Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, USA. ·Hear Res · Pubmed #22016077.

ABSTRACT: Our understanding of hereditary hearing loss has greatly improved since the discovery of the first human deafness gene. These discoveries have only accelerated due to the great strides in DNA sequencing technology since the completion of the human genome project. Here, we review the immense impact that these developments have had in both deafness research and clinical arenas. We review commonly used genomic technologies as well as the application of these technologies to the genetic diagnosis of hereditary hearing loss and to the discovery of novel deafness genes.

8 Review Genetic disorders of the vestibular system. 2011

Eppsteiner, Robert W / Smith, Richard J H. ·Department of Otolaryngology - Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA. ·Curr Opin Otolaryngol Head Neck Surg · Pubmed #21825995.

ABSTRACT: PURPOSE OF REVIEW: This review highlights the current body of literature related to the genetics of inherited vestibular disorders and provides a framework for the characterization of these disorders. We emphasize peripheral causes of vestibular dysfunction and highlight recent advances in the field, point out gaps in understanding, and focus on key areas for future investigation. RECENT FINDINGS: The discovery of a modifier gene that leads to a more severe Usher syndrome phenotype calls into question the assumption that Usher syndrome is universally a monogenic disorder. Despite the use of several investigational approaches, the genetic basis of Menière's disease remains poorly understood. Evidence for a vestibular phenotype associated with DFNB1 suggests that mutations in other genes causally related to nonsyndromic hearing loss also may have an unrecognized vestibular phenotype. SUMMARY: Our understanding of the genetic basis for vestibular disorders is superficial. Significant challenges include defining the genetics of inherited isolated vestibular dysfunction and understanding the pathological basis of Menière's disease. However, improved characterization of inherited vestibular dysfunction, coupled with advanced genetic techniques such as targeted genome capture and massively parallel sequencing, provides an opportunity to investigate these diseases at the genetic level.

9 Review Two Iranian families with a novel mutation in GJB2 causing autosomal dominant nonsyndromic hearing loss. 2011

Bazazzadegan, Niloofar / Sheffield, Abraham M / Sobhani, Masoomeh / Kahrizi, Kimia / Meyer, Nicole C / Van Camp, Guy / Hilgert, Nele / Abedini, Seyedeh Sedigheh / Habibi, Farkhondeh / Daneshi, Ahmad / Nishimura, Carla / Avenarius, Matthew R / Farhadi, Mohammad / Smith, Richard J H / Najmabadi, Hossein. ·Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. ·Am J Med Genet A · Pubmed #21484990.

ABSTRACT: Mutations in GJB2, encoding connexin 26 (Cx26), cause both autosomal dominant and autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNA3 and DFNB1 loci, respectively. Most of the over 100 described GJB2 mutations cause ARNSHL. Only a minority has been associated with autosomal dominant hearing loss. In this study, we present two families with autosomal dominant nonsyndromic hearing loss caused by a novel mutation in GJB2 (p.Asp46Asn). Both families were ascertained from the same village in northern Iran consistent with a founder effect. This finding implicates the D46N missense mutation in Cx26 as a common cause of deafness in this part of Iran mandating mutation screening of GJB2 for D46N in all persons with hearing loss who originate from this geographic region.

10 Review A contemporary review of AudioGene audioprofiling: a machine-based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss. 2009

Hildebrand, Michael S / DeLuca, Adam P / Taylor, Kyle R / Hoskinson, David P / Hur, In Ae / Tack, Dylan / McMordie, Sarah J / Huygen, Patrick L M / Casavant, Thomas L / Smith, Richard J H. ·Department of Otolaryngology-Head and Neck Surgery, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. ·Laryngoscope · Pubmed #19780026.

ABSTRACT: -- No abstract --

11 Review Function and expression pattern of nonsyndromic deafness genes. 2009

Hilgert, Nele / Smith, Richard J H / Van Camp, Guy. ·Department of Medical Genetics, University of Antwerp (UA), Belgium. ·Curr Mol Med · Pubmed #19601806.

ABSTRACT: Hearing loss is the most common sensory disorder, present in 1 of every 500 newborns. To date, 46 genes have been identified that cause nonsyndromic hearing loss, making it an extremely heterogeneous trait. This review provides a comprehensive overview of the inner ear function and expression pattern of these genes. In general, they are involved in hair bundle morphogenesis, form constituents of the extracellular matrix, play a role in cochlear ion homeostasis or serve as transcription factors. During the past few years, our knowledge of genes involved in hair bundle morphogenesis has increased substantially. We give an up-to-date overview of both the nonsyndromic and Usher syndrome genes involved in this process, highlighting proteins that interact to form macromolecular complexes. For every gene, we also summarize its expression pattern and impact on hearing at the functional level. Gene-specific cochlear expression is summarized in a unique table by structure/cell type and is illustrated on a cochlear cross-section, which is available online via the Hereditary Hearing Loss Homepage. This review should provide auditory scientists the most relevant information for all identified nonsyndromic deafness genes.

12 Review Therapeutic regulation of gene expression in the inner ear using RNA interference. 2009

Maeda, Yukihide / Sheffield, Abraham M / Smith, Richard J H. · ·Adv Otorhinolaryngol · Pubmed #19494570.

ABSTRACT: Targeting and downregulating specific genes with antisense and decoy oligonucleotides, ribozymes or RNA interference (RNAi) offer the theoretical potential of altering a disease phenotype. Here we review the molecular mechanism behind the in vivo application of RNAi-mediated gene silencing, focusing on its application to the inner ear. RNAi is a physiological phenomenon in which small, double-stranded RNA molecules (small interfering RNA, siRNA) reduce expression of homologous genes. Notable for its exquisite sequence specificity, it is ideally applied to diseases caused by a gain-of-function mechanism of action. Types of deafness in which gain-of-function mutations are observed include DFNA2 (KCNQ4), DFNA3 (GJB2) and DFNA5 (DFNA5). Several strategies can be used to deliver siRNA into the inner ear, including cationic liposomes, adeno-associated and lentiviral vectors, and adenoviral vectors. Transduction efficiency with cationic liposomes is low and the effect is transient; with adeno-associated and lentiviral vectors, long-term transfection is possible using a small hairpin RNA expression cassette.

13 Article Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. 2019

Booth, Kevin T / Askew, James W / Talebizadeh, Zohreh / Huygen, Patrick L M / Eudy, James / Kenyon, Judith / Hoover, Denise / Hildebrand, Michael S / Smith, Katherine R / Bahlo, Melanie / Kimberling, William J / Smith, Richard J H / Azaiez, Hela / Smith, Shelley D. ·Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA. · Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. · Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA. · Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA. · Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. · DNA Microarray and Sequencing Core, University of Nebraska Medical Center, Omaha, NE, USA. · Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia. · The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. · Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA, USA. hela-azaiez@uiowa.edu. · Developmental Neuroscience, Munroe Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA. shelley.smith@unmc.edu. ·Genet Med · Pubmed #30245514.

ABSTRACT: PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing. CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.

14 Article Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. 2018

Azaiez, Hela / Booth, Kevin T / Ephraim, Sean S / Crone, Bradley / Black-Ziegelbein, Elizabeth A / Marini, Robert J / Shearer, A Eliot / Sloan-Heggen, Christina M / Kolbe, Diana / Casavant, Thomas / Schnieders, Michael J / Nishimura, Carla / Braun, Terry / Smith, Richard J H. ·Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Center for Bioinformatics and Computational Biology, Departments of Electrical and Computer Engineering and Biomedical Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USA. · Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA 52242, USA. Electronic address: richard-smith@uiowa.edu. ·Am J Hum Genet · Pubmed #30245029.

ABSTRACT: The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.

15 Article Grxcr2 is required for stereocilia morphogenesis in the cochlea. 2018

Avenarius, Matthew R / Jung, Jae-Yun / Askew, Charles / Jones, Sherri M / Hunker, Kristina L / Azaiez, Hela / Rehman, Atteeq U / Schraders, Margit / Najmabadi, Hossein / Kremer, Hannie / Smith, Richard J H / Géléoc, Gwenaëlle S G / Dolan, David F / Raphael, Yehoash / Kohrman, David C. ·Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America. · Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America. · Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, United States of America. · Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Communication Sciences and Disorders, East Carolina University, Greenville, North Carolina, United States of America. · Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America. · Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, United States of America. · Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands. · Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. ·PLoS One · Pubmed #30157177.

ABSTRACT: Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity.

16 Article CDC14A phosphatase is essential for hearing and male fertility in mouse and human. 2018

Imtiaz, Ayesha / Belyantseva, Inna A / Beirl, Alisha J / Fenollar-Ferrer, Cristina / Bashir, Rasheeda / Bukhari, Ihtisham / Bouzid, Amal / Shaukat, Uzma / Azaiez, Hela / Booth, Kevin T / Kahrizi, Kimia / Najmabadi, Hossein / Maqsood, Azra / Wilson, Elizabeth A / Fitzgerald, Tracy S / Tlili, Abdelaziz / Olszewski, Rafal / Lund, Merete / Chaudhry, Taimur / Rehman, Atteeq U / Starost, Matthew F / Waryah, Ali M / Hoa, Michael / Dong, Lijin / Morell, Robert J / Smith, Richard J H / Riazuddin, Sheikh / Masmoudi, Saber / Kindt, Katie S / Naz, Sadaf / Friedman, Thomas B. ·Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. · School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan. · Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. · Laboratory of Molecular and Cellular Neurobiology, Section on Molecular and Cellular Signaling, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA. · Laboratoire Procédés de Criblage Moléculaire et Cellulaire, Centre de Biotechnologie de Sfax, Université de Sfax, Sfax 3451, Tunisia. · Center of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, Pakistan. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology - Head and Neck Surgery, University of Iowa, Iowa City, 52242, IA, USA. · The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, 52242, IA, USA. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1987513834, Iran. · Mouse Auditory Testing Core Facility, NIH, Bethesda, MD 20892, USA. · Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. · Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, USA. · Genetic Engineering Core, National Eye Institute, NIH, Bethesda, MD 20892, USA. · Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA. · Pakistan Institute of Medical Sciences, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan. · Laboratory for Research in Genetic Diseases, Burn Centre, Allama Iqbal Medical College, University of Health Sciences, Lahore 54590, Pakistan. ·Hum Mol Genet · Pubmed #29293958.

ABSTRACT: The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate Cell Division-Cycle-14 (CDC14A) have been proposed largely based on studies of cultured cancer cells in vitro. The in vivo functions of vertebrate CDC14A are largely unknown. We generated and analyzed mutations of zebrafish and mouse CDC14A, developed a computational structural model of human CDC14A protein and report four novel truncating and three missense alleles of CDC14A in human families segregating progressive, moderate-to-profound deafness. In five of these families segregating pathogenic variants of CDC14A, deaf males are infertile, while deaf females are fertile. Several recessive mutations of mouse Cdc14a, including a CRISPR/Cas9-edited phosphatase-dead p.C278S substitution, result in substantial perinatal lethality, but survivors recapitulate the human phenotype of deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies and sound-transducing stereocilia. Auditory hair cells of postnatal Cdc14a mutants develop normally, but subsequently degenerate causing deafness. Kinocilia of germ-line mutants of mouse and zebrafish have normal lengths, which does not recapitulate the published cdc14aa knockdown morphant phenotype of short kinocilia. In mutant male mice, degeneration of seminiferous tubules and spermiation defects result in low sperm count, and abnormal sperm motility and morphology. These findings for the first time define a new monogenic syndrome of deafness and male infertility revealing an absolute requirement in vivo of vertebrate CDC14A phosphatase activity for hearing and male fertility.

17 Article CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. 2017

Michel, Vincent / Booth, Kevin T / Patni, Pranav / Cortese, Matteo / Azaiez, Hela / Bahloul, Amel / Kahrizi, Kimia / Labbé, Ménélik / Emptoz, Alice / Lelli, Andrea / Dégardin, Julie / Dupont, Typhaine / Aghaie, Asadollah / Oficjalska-Pham, Danuta / Picaud, Serge / Najmabadi, Hossein / Smith, Richard J / Bowl, Michael R / Brown, Steven Dm / Avan, Paul / Petit, Christine / El-Amraoui, Aziz. ·Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France. · Unité Mixte de Recherche- UMRS 1120, Institut National de la Santé et de la Recherche Médicale, Paris, France. · Sorbonne Universités, UPMC Univ Paris06, Paris, France. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology- Head and Neck Surgery, University of Iowa, Iowa City, Iowa. · Department of Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. · Retinal information processing - Pharmacology and Pathology, Institut de la Vision, Paris, France. · Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, Paris, France. · Mammalian Genetics Unit, MRC Harwell Institute, Oxford, UK. · Laboratoire de Biophysique Sensorielle, Faculté de Médecine, Biophysique Médicale, Centre Jean Perrin, Université d'Auvergne, Clermont-Ferrand, France. · Collège de France, Paris, France. · Génétique et Physiologie de l'Audition, Institut Pasteur, Paris, France aziz.el-amraoui@pasteur.fr. ·EMBO Mol Med · Pubmed #29084757.

ABSTRACT: Defects of CIB2, calcium- and integrin-binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type-IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in

18 Article Screening of deafness-causing DNA variants that are common in patients of European ancestry using a microarray-based approach. 2017

Yan, Denise / Xiang, Guangxin / Chai, Xingping / Qing, Jie / Shang, Haiqiong / Zou, Bing / Mittal, Rahul / Shen, Jun / Smith, Richard J H / Fan, Yao-Shan / Blanton, Susan H / Tekin, Mustafa / Morton, Cynthia / Xing, Wanli / Cheng, Jing / Liu, Xue Zhong. ·Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida, United States of America. · National Engineering Research Center for Beijing Biochip Technology, Beijing, China. · Tsinghua University School of Medicine, Beijing, China. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, Massachusetts, United States of America. · Department of Otolaryngology - Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America. · Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America. · Dr. John T. Macdonald Department of Human Genetics and John P.Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America. · Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Division of Evolution and Genomic Science, School of Biological Sciences, Manchester Academic Health Science Center, University of Manchester, United Kingdom. ·PLoS One · Pubmed #28273078.

ABSTRACT: The unparalleled heterogeneity in genetic causes of hearing loss along with remarkable differences in prevalence of causative variants among ethnic groups makes single gene tests technically inefficient. Although hundreds of genes have been reported to be associated with nonsyndromic hearing loss (NSHL), GJB2, GJB6, SLC26A4, and mitochondrial (mt) MT-RNR1 and MTTS are the major contributors. In order to provide a faster, more comprehensive and cost effective assay, we constructed a DNA fluidic array, CapitalBioMiamiOtoArray, for the detection of sequence variants in five genes that are common in most populations of European descent. They consist of c.35delG, p.W44C, p.L90P, c.167delT (GJB2); 309kb deletion (GJB6); p.L236P, p.T416P (SLC26A4); and m.1555A>G, m.7444G>A (mtDNA). We have validated our hearing loss array by analyzing a total of 160 DNAs samples. Our results show 100% concordance between the fluidic array biochip-based approach and the established Sanger sequencing method, thus proving its robustness and reliability at a relatively low cost.

19 Article Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. 2017

Shearer, A Eliot / Eppsteiner, Robert W / Frees, Kathy / Tejani, Viral / Sloan-Heggen, Christina M / Brown, Carolyn / Abbas, Paul / Dunn, Camille / Hansen, Marlan R / Gantz, Bruce J / Smith, Richard J H. ·Department of Otolaryngology-Head & Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Otolaryngology-Head & Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Communication Sciences & Disorders, University of Iowa, Iowa City, IA, USA. · Department of Otolaryngology-Head & Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, IA, USA; Department of Molecular Physiology & Biophysics, University of Iowa College of Medicine, Iowa City, IA, USA. Electronic address: richard-smith@uiowa.edu. ·Hear Res · Pubmed #28213135.

ABSTRACT: BACKGROUND: Cochlear implantation is an effective habilitation modality for adults with significant hearing loss. However, post-implant performance is variable. A portion of this variance in outcome can be attributed to clinical factors. Recent physiological studies suggest that the health of the spiral ganglion also impacts post-operative cochlear implant outcomes. The goal of this study was to determine whether genetic factors affecting spiral ganglion neurons may be associated with cochlear implant performance. METHODS: Adults with post-lingual deafness who underwent cochlear implantation at the University of Iowa were studied. Pre-implantation evaluation included comprehensive genetic testing for genetic diagnosis. A novel score of genetic variants affecting genes with functional effects in the spiral ganglion was calculated. A Z-scored average of up to three post-operative speech perception tests (CNC, HINT, and AzBio) was used to assess outcome. RESULTS: Genetically determined spiral ganglion health affects cochlear implant outcomes, and when considered in conjunction with clinically determined etiology of deafness, accounts for 18.3% of the variance in postoperative speech recognition outcomes. Cochlear implant recipients with deleterious genetic variants that affect the cochlear sensory organ perform significantly better on tests of speech perception than recipients with deleterious genetic variants that affect the spiral ganglion. CONCLUSION: Etiological diagnosis of deafness including genetic testing is the single largest predictor of postoperative speech outcomes in adult cochlear implant recipients. A detailed understanding of the genetic underpinning of hearing loss will better inform pre-implant counseling. The method presented here should serve as a guide for further research into the molecular physiology of the peripheral auditory system and cochlear implants.

20 Article A novel mutation in ACTG1 causing Baraitser-Winter syndrome with extremely variable expressivity in three generations. 2017

Kemerley, Andrew / Sloan, Christina / Pfeifer, Wanda / Smith, Richard / Drack, Arlene. ·a Department of Ophthalmology and Visual Sciences , University of Iowa , Iowa City , Iowa , USA. · b Department of Otolaryngology , University of Iowa , Iowa City , Iowa , USA. ·Ophthalmic Genet · Pubmed #27096712.

ABSTRACT: Baraitser-Winter syndrome (cerebrofrontofacial syndrome, type 3) is a rare developmental disorder typified by hypertelorism, ptosis, high-arched eyebrows, ocular coloboma, and brain malformations. Other common manifestations include hearing loss, short stature, seizures, intellectual impairment, muscle dysfunction, and abnormalities of the kidney and urinary system. This syndrome is caused by missense mutations in the genes ACTB or ACTG1, both of which encode for cytoplasmic actin proteins crucial for proper development of many organs in the human body. There are no reports of familial transmission; all reported cases have been new mutations. However, different mutations in ACTG1 have been reported to cause isolated non-syndromic hearing loss, with many reported cases of autosomal dominant (AD) inheritance. We have identified a three-generation pedigree segregating a novel mutation in the ACTG1 gene that causes Baraitser-Winter Syndrome with extremely variable expressivity, leading to an initial diagnosis of isolated AD hearing loss in two members. Subtle optic nerve signs not previously reported in this syndrome are also documented in one patient.

21 Article Detection and Confirmation of Deafness-Causing Copy Number Variations in the STRC Gene by Massively Parallel Sequencing and Comparative Genomic Hybridization. 2016

Moteki, Hideaki / Azaiez, Hela / Sloan-Heggen, Christina M / Booth, Kevin / Nishio, Shin-Ya / Wakui, Keiko / Yamaguchi, Tomomi / Kolbe, Diana L / Iwasa, Yoh-Ichiro / Shearer, A Eliot / Fukushima, Yoshimitsu / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospital and Clinics, Iowa, USA. · Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospital and Clinics, Iowa, USA. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #27469136.

ABSTRACT: OBJECTIVE: Copy number variations (CNVs), a major cause of genetic hearing loss, most frequently involve the STRC gene, located on chr15q15.3 and causally related to autosomal recessive non-syndromic hearing loss (ARNSHL) at the DFNB16 locus. The interpretation of STRC sequence data can be challenging due to the existence of a virtually identical pseudogene, pSTRC, that promotes complex genomic rearrangements in this genomic region. Targeted genomic enrichment with massively parallel sequencing (TGE+MPS) has emerged as the preferred method by which to provide comprehensive genetic testing for hearing loss. We aimed to identify CNVs in the STRC region using established and validated bioinformatics methods. METHODS: We used TGE+MPS to identify the genetic cause of hearing loss. The CNV results were confirmed with customized array comparative genomic hybridization (array CGH). RESULTS: Three probands with progressive mild to moderate hearing loss were found among 40 subjects with ARNSHL to segregate homozygous STRC deletions and gene to pseudogene conversion. Array CGH showed that the deletions/conversions span multiple genes outside of the exons captured by TGE+MPS. CONCLUSION: These data further validate the necessity to integrate the detection of both simple variant changes and complex genomic rearrangements in the clinical diagnosis of genetic hearing loss.

22 Article RNA Interference Prevents Autosomal-Dominant Hearing Loss. 2016

Shibata, Seiji B / Ranum, Paul T / Moteki, Hideaki / Pan, Bifeng / Goodwin, Alexander T / Goodman, Shawn S / Abbas, Paul J / Holt, Jeffrey R / Smith, Richard J H. ·Department of Otolaryngology - Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Molecular & Cellular Biology, Graduate College, University of Iowa, Iowa City, IA 52242, USA. · Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Nagano 3908621, Japan. · Department of Otolaryngology, F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. · Department of Communication Sciences and Disorders, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA. · Department of Otolaryngology - Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Molecular & Cellular Biology, Graduate College, University of Iowa, Iowa City, IA 52242, USA; Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: richard-smith@uiowa.edu. ·Am J Hum Genet · Pubmed #27236922.

ABSTRACT: Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

23 Article Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. 2016

Sloan-Heggen, Christina M / Bierer, Amanda O / Shearer, A Eliot / Kolbe, Diana L / Nishimura, Carla J / Frees, Kathy L / Ephraim, Sean S / Shibata, Seiji B / Booth, Kevin T / Campbell, Colleen A / Ranum, Paul T / Weaver, Amy E / Black-Ziegelbein, E Ann / Wang, Donghong / Azaiez, Hela / Smith, Richard J H. ·Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA. · Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, 52242, IA, USA. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA. richard-smith@uiowa.edu. · Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, 52242, IA, USA. richard-smith@uiowa.edu. · Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, 52242, IA, USA. richard-smith@uiowa.edu. ·Hum Genet · Pubmed #26969326.

ABSTRACT: Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39%). Pathogenic variants were found in 49 genes and included missense variants (49%), large copy number changes (18%), small insertions and deletions (18%), nonsense variants (8%), splice-site alterations (6%), and promoter variants (<1%). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.

24 Article Audioprofile Surfaces: The 21st Century Audiogram. 2016

Taylor, Kyle R / Booth, Kevin T / Azaiez, Hela / Sloan, Christina M / Kolbe, Diana L / Glanz, Emily N / Shearer, A Eliot / DeLuca, Adam P / Anand, V Nikhil / Hildebrand, Michael S / Simpson, Allen C / Eppsteiner, Robert W / Scheetz, Todd E / Braun, Terry A / Huygen, Patrick L M / Smith, Richard J H / Casavant, Thomas L. ·Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa, USA Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USA. · Department of Otolaryngology, Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA. · Department of Molecular Physiology and Biophysics, University of Iowa Carver, Iowa City, Iowa, USA. · Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, USA. · Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USA. · Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa, USA Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa, USA Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, USA. · Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Department of Otolaryngology, Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA Department of Molecular Physiology and Biophysics, University of Iowa Carver, Iowa City, Iowa, USA richard-smith@uiowa.edu. ·Ann Otol Rhinol Laryngol · Pubmed #26530094.

ABSTRACT: OBJECTIVE: To present audiometric data in 3 dimensions by considering age as an addition dimension. METHODS: Audioprofile surfaces (APSs) were fitted to a set of audiograms by plotting each measurement of an audiogram as an independent point in 3 dimensions with the x, y, and z axes representing frequency, hearing loss in dB, and age, respectively. RESULTS: Using the Java-based APS viewer as a standalone application, APSs were pre-computed for 34 loci. By selecting APSs for the appropriate genetic locus, a clinician can compare this APS-generated average surface to a specific patient's audiogram. CONCLUSION: Audioprofile surfaces provide an easily interpreted visual representation of a person's hearing acuity relative to others with the same genetic cause of hearing loss. Audioprofile surfaces will support the generation and testing of sophisticated hypotheses to further refine our understanding of the biology of hearing.

25 Article Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran. 2015

Sloan-Heggen, Christina M / Babanejad, Mojgan / Beheshtian, Maryam / Simpson, Allen C / Booth, Kevin T / Ardalani, Fariba / Frees, Kathy L / Mohseni, Marzieh / Mozafari, Reza / Mehrjoo, Zohreh / Jamali, Leila / Vaziri, Saeideh / Akhtarkhavari, Tara / Bazazzadegan, Niloofar / Nikzat, Nooshin / Arzhangi, Sanaz / Sabbagh, Farahnaz / Otukesh, Hasan / Seifati, Seyed Morteza / Khodaei, Hossein / Taghdiri, Maryam / Meyer, Nicole C / Daneshi, Ahmad / Farhadi, Mohammad / Kahrizi, Kimia / Smith, Richard J H / Azaiez, Hela / Najmabadi, Hossein. ·Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. · Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. · Genetics Counseling Center, Kerman Welfare Institution, Kerman, Iran. · Division of Pediatric Nephrology, Hazrat-e-Ali Asghar Educational & Treatment Center, Iran University of Medical Sciences, Tehran, Iran. · Meybod Genetics Research Center, Shahid Fiazbakhsh Rehabilitation Comprehensive Center, Welfare Organization, Yazd, Iran. · Genetic Counseling Center, Shiraz Welfare Institution, Shiraz, Iran. · Head and Neck Surgery Department and Research Center, Iran University of Medical Sciences, Tehran, Iran. · Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, USA. ·J Med Genet · Pubmed #26445815.

ABSTRACT: BACKGROUND: Countries 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, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. DESIGN: Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. RESULTS: We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. CONCLUSION: This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.

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