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Hearing Disorders: HELP
Articles by Hela Azaiez
Based on 26 articles published since 2010
(Why 26 articles?)
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Between 2010 and 2020, H. Azaiez wrote the following 26 articles about Hearing Disorders.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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.

2 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.

3 Article Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. 2018

Oza, Andrea M / DiStefano, Marina T / Hemphill, Sarah E / Cushman, Brandon J / Grant, Andrew R / Siegert, Rebecca K / Shen, Jun / Chapin, Alex / Boczek, Nicole J / Schimmenti, Lisa A / Murry, Jaclyn B / Hasadsri, Linda / Nara, Kiyomitsu / Kenna, Margaret / Booth, Kevin T / Azaiez, Hela / Griffith, Andrew / Avraham, Karen B / Kremer, Hannie / Rehm, Heidi L / Amr, Sami S / Abou Tayoun, Ahmad N / Anonymous8740964. ·Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts. · Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts. · ARUP Laboratories, Salt Lake City, Utah. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. · Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, Iowa. · The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa. · Audiology Unit, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland. · Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. · Department of Otorhinolaryngology and Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts. · The Broad Institute of MIT and Harvard, Cambridge, Massachusetts. · The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. · The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. ·Hum Mutat · Pubmed #30311386.

ABSTRACT: Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.

4 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.

5 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.

6 Article Old gene, new phenotype: splice-altering variants in 2018

Booth, Kevin T / Kahrizi, Kimia / Najmabadi, Hossein / Azaiez, Hela / Smith, Richard Jh. ·Molecular Otolaryngology Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, Iowa, USA. · The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Islamic Republic of Iran. ·J Med Genet · Pubmed #29703829.

ABSTRACT: BACKGROUND: Hearing loss is a genetically and phenotypically heterogeneous disorder. OBJECTIVES: The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families. METHODS: We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays. RESULTS: We identified two homozygous splice-altering variants (c.37G>T and c.662-1G>C) in the CONCLUSIONS: These results suggest that loss-of-function mutations in

7 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.

8 Article Variants in CIB2 cause DFNB48 and not USH1J. 2018

Booth, K T / Kahrizi, K / Babanejad, M / Daghagh, H / Bademci, G / Arzhangi, S / Zareabdollahi, D / Duman, D / El-Amraoui, A / Tekin, M / Najmabadi, H / Azaiez, H / Smith, R J. ·Department of Otolaryngology, Head and Neck Surgery, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, USA. · Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. · John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. · Division of Pediatric Genetics, Ankara University School of Medicine, Ankara, Turkey. · Institut Pasteur, Génétique et Physiologie de l'Audition, Paris, France. · John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA. ·Clin Genet · Pubmed #29112224.

ABSTRACT: The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.

9 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

10 Article Advances in Molecular Genetics and the Molecular Biology of Deafness. 2016

Nishio, Shin-Ya / Schrauwen, Isabelle / Moteki, Hideaki / Azaiez, Hela. ·Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan. · Translational Genomics Research Institute, Phoenix, AZ 85004, USA. · Department of Otolaryngology, University of Iowa, Iowa City, IA 52246, USA. ·Biomed Res Int · Pubmed #27525271.

ABSTRACT: -- No abstract --

11 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.

12 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.

13 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.

14 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.

15 Article PDZD7 and hearing loss: More than just a modifier. 2015

Booth, Kevin T / Azaiez, Hela / Kahrizi, Kimia / Simpson, Allen C / Tollefson, William T A / Sloan, Christina M / Meyer, Nicole C / Babanejad, Mojgan / Ardalani, Fariba / Arzhangi, Sanaz / Schnieders, Michael J / Najmabadi, Hossein / Smith, Richard J H. ·Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa. · Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. · Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa. ·Am J Med Genet A · Pubmed #26416264.

ABSTRACT: Deafness is the most frequent sensory disorder. With over 90 genes and 110 loci causally implicated in non-syndromic hearing loss, it is phenotypically and genetically heterogeneous. Here, we investigate the genetic etiology of deafness in four families of Iranian origin segregating autosomal recessive non-syndromic hearing loss (ARNSHL). We used a combination of linkage analysis, homozygosity mapping, and a targeted genomic enrichment platform to simultaneously screen 90 known deafness-causing genes for pathogenic variants. Variant segregation was confirmed by Sanger sequencing. Linkage analysis and homozygosity mapping showed segregation with the DFNB57 locus on chromosome 10 in two families. Targeted genomic enrichment with massively parallel sequencing identified causal variants in PDZD7: a homozygous missense variant (p.Gly103Arg) in one family and compound heterozygosity for missense (p.Met285Arg) and nonsense (p.Tyr500Ter) variants in the second family. Screening of two additional families identified two more variants: (p.Gly228Arg) and (p.Gln526Ter). Variant segregation with the hearing loss phenotype was confirmed in all families by Sanger sequencing. The missense variants are predicted to be deleterious, and the two nonsense mutations produce null alleles. This report is the first to show that mutations in PDZD7 cause ARNSHL, a finding that offers addition insight into the USH2 interactome. We also describe a novel likely disease-causing mutation in CIB2 and illustrate the complexity associated with gene identification in diseases that exhibit large genetic and phenotypic heterogeneity.

16 Article HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. 2015

Azaiez, Hela / Decker, Amanda R / Booth, Kevin T / Simpson, Allen C / Shearer, A Eliot / Huygen, Patrick L M / Bu, Fengxiao / Hildebrand, Michael S / Ranum, Paul T / Shibata, Seiji B / Turner, Ann / Zhang, Yuzhou / Kimberling, William J / Cornell, Robert A / Smith, Richard J H. ·Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America. · Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America. · Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. · Austin Health, Department of Medicine, University of Melbourne, Melbourne, Australia. · Self-employed physician, Menlo Park, California, United States of America. · Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology University of Iowa, Iowa City, Iowa, United States of America; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America. ·PLoS Genet · Pubmed #25816005.

ABSTRACT: Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over-expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action.

17 Article Mutations in LOXHD1 gene cause various types and severities of hearing loss. 2015

Mori, Kentaro / Moteki, Hideaki / Kobayashi, Yumiko / Azaiez, Hela / Booth, Kevin T / Nishio, Shin-Ya / Sato, Hiroaki / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · Department of Otolaryngology, Iwate Medical University School of Medicine, Iwate, Japan. · Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · Department of Otolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #25792669.

ABSTRACT: OBJECTIVE: We present 2 families that were identified with novel mutations in LOXHD1 as a cause of nonprogressive hearing loss. METHODS: One thousand three hundred fourteen (1314) Japanese subjects with sensorineural hearing loss from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic cause of hearing loss. RESULTS: Two patients in 1 family affected with homozygous mutation c.879+1G>A in LOXHD1 showed profound congenital hearing loss, whereas 2 patients in another family with compound heterozygous mutations, c.5869G>T (p.E1957X) and c.4480C>T (p.R1494X), showed moderate to severe hearing loss. CONCLUSION: Mutations in LOXHD1 are extremely rare, and these cases are the first identified in a Japanese population. The genotype-phenotype correlation in LOXHD1 is still unclear. The differences in phenotypes in each patient might be the result of the nature of the mutations or the location on the gene, or be influenced by a genetic modifier.

18 Article De novo mutation in X-linked hearing loss-associated POU3F4 in a sporadic case of congenital hearing loss. 2015

Moteki, Hideaki / Shearer, A Eliot / Izumi, Shuji / Kubota, Yamato / Azaiez, Hela / Booth, Kevin T / Sloan, Christina M / Kolbe, Diana L / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · Department of Otolaryngology-Head and Neck Surgery, Niigata University Faculty of Medicine, Niigata, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #25792666.

ABSTRACT: OBJECTIVES: In this report, we present a male patient with no family history of hearing loss, in whom we identified a novel de novo mutation in the POU3F4 gene. METHODS: One hundred ninety-four (194) Japanese subjects from unrelated and nonconsanguineous families were enrolled in this study. We used targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes for identifying the genetic causes of hearing loss. RESULTS: A novel de novo frameshift mutation of POU3F4 to c.727_728insA (p.N244KfsX26) was identified. The patient was a 7-year-old male with congenital progressive hearing loss and inner ear deformity. Although the patient had received a cochlear implant, auditory skills were still limited. The patient also exhibited developmental delays similar to those previously associated with POU3F4 mutation. CONCLUSION: This is the first report of a mutation in POU3F4 causing hearing loss in a Japanese patient without a family history of hearing loss. This study underscores the importance of comprehensive genetic testing of patients with hearing loss for providing accurate prognostic information and guiding the optimal management of patient rehabilitation.

19 Article Novel PTPRQ mutations identified in three congenital hearing loss patients with various types of hearing loss. 2015

Sakuma, Naoko / Moteki, Hideaki / Azaiez, Hela / Booth, Kevin T / Takahashi, Masahiro / Arai, Yasuhiro / Shearer, A Eliot / Sloan, Christina M / Nishio, Shin-Ya / Kolbe, Diana L / Iwasaki, Satoshi / Oridate, Nobuhiko / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otorhinolaryngology and Head and Neck Surgery, Yokohama City University School of Medicine, Yokohama, Japan Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · Department of Otorhinolaryngology and Head and Neck Surgery, Yokohama City University School of Medicine, Yokohama, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan Department of Otorhinolaryngology, International University of Health and Welfare, Mita Hospital, Minatoku, Tokyo, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #25788564.

ABSTRACT: OBJECTIVES: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. METHODS: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. RESULTS: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. CONCLUSION: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.

20 Article Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation. 2015

Moteki, Hideaki / Azaiez, Hela / Booth, Kevin T / Hattori, Mitsuru / Sato, Ai / Sato, Yoshihiko / Motobayashi, Mitsuo / Sloan, Christina M / Kolbe, Diana L / Shearer, A Eliot / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Division of Diabetes, Endocrinology and Metabolism: Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #25788561.

ABSTRACT: OBJECTIVES: We present a family with a mitochondrial DNA 3243A>G mutation resulting in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), of which some members have hearing loss in which a novel mutation in the P2RX2 gene was identified. METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss. RESULTS: A novel mutation in the P2RX2 gene that corresponded to c.601G>A (p.Asp201Tyr) was identified. Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing. CONCLUSION: This is the first case report of a diagnosis of hearing loss caused by P2RX2 mutation in patients with MELAS. A potential explanation is that a decrease in adenosine triphosphate (ATP) production due to MELAS with a mitochondrial 3243A>G mutation might suppress activation of P2X2 receptors. We also suggest that hearing loss caused by the P2RX2 mutation might be influenced by the decrease in ATP production due to MELAS.

21 Article USH2 caused by GPR98 mutation diagnosed by massively parallel sequencing in advance of the occurrence of visual symptoms. 2015

Moteki, Hideaki / Yoshimura, Hidekane / Azaiez, Hela / Booth, Kevin T / Shearer, A Eliot / Sloan, Christina M / Kolbe, Diana L / Murata, Toshinori / Smith, Richard J H / Usami, Shin-Ichi. ·Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otolaryngology-Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. · Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan usami@shinshu-u.ac.jp. ·Ann Otol Rhinol Laryngol · Pubmed #25743181.

ABSTRACT: OBJECTIVE: We present 2 patients who were identified with mutations in the GPR98 gene that causes Usher syndrome type 2 (USH2). METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were used to identify the genetic causes of hearing loss. RESULTS: We identified causative mutations in the GPR98 gene in 1 family (2 siblings). The patients had moderate sloping hearing loss, and no progression was observed over a period of 10 years. Fundus examinations were normal. However, electroretinograms revealed impaired responses in both patients. CONCLUSION: Early diagnosis of Usher syndrome has many advantages for patients and their families. This study supports the use of comprehensive genetic diagnosis for Usher syndrome, especially prior to the onset of visual symptoms, to provide the highest chance of diagnostic success in early life stages.

22 Article Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. 2014

Shearer, A Eliot / Eppsteiner, Robert W / Booth, Kevin T / Ephraim, Sean S / Gurrola, José / Simpson, Allen / Black-Ziegelbein, E Ann / Joshi, Swati / Ravi, Harini / Giuffre, Angelica C / Happe, Scott / Hildebrand, Michael S / Azaiez, Hela / Bayazit, Yildirim A / Erdal, Mehmet Emin / Lopez-Escamez, Jose A / Gazquez, Irene / Tamayo, Marta L / Gelvez, Nancy Y / Leal, Greizy Lopez / Jalas, Chaim / Ekstein, Josef / Yang, Tao / Usami, Shin-ichi / Kahrizi, Kimia / Bazazzadegan, Niloofar / Najmabadi, Hossein / Scheetz, Todd E / Braun, Terry A / Casavant, Thomas L / LeProust, Emily M / Smith, Richard J H. ·Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. · Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA. · Agilent Technologies, Cedar Creek, TX 78612, USA. · Epilepsy Research Centre, Department of Medicine, University of Melbourne, Heidelberg, VIC 3084, Australia. · Department of Otolaryngology, Faculty of Medicine, Medipol University, Istanbul 34083, Turkey. · Department of Medical Biology and Genetics, University of Mersin, Mersin 33160, Turkey. · Otology and Neurotology Group CTS495, Center for Genomic and Oncological Research (GENyO), Granada 18012, Spain. · Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia. · Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY 11204, USA. · Dor Yeshorim, The Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY 11211, USA. · Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, and the Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China. · Department of Otorhinolaryngology, School of Medicine, Shinshu University, Matsumoto, Nagano 390-8621, Japan. · Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran. · Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA; Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA. · Molecular Otolaryngology & Renal Research Labs, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, IA 52242, USA; Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: richard-smith@uiowa.edu. ·Am J Hum Genet · Pubmed #25262649.

ABSTRACT: Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.

23 Article TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. 2014

Azaiez, Hela / Booth, Kevin T / Bu, Fengxiao / Huygen, Patrick / Shibata, Seiji B / Shearer, A Eliot / Kolbe, Diana / Meyer, Nicole / Black-Ziegelbein, E Ann / Smith, Richard J H. ·Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa. ·Hum Mutat · Pubmed #24729539.

ABSTRACT: Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal-dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole-exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders.

24 Article A novel DFNB1 deletion allele supports the existence of a distant cis-regulatory region that controls GJB2 and GJB6 expression. 2010

Wilch, E / Azaiez, H / Fisher, R A / Elfenbein, J / Murgia, A / Birkenhäger, R / Bolz, H / Da Silva-Costa, S M / Del Castillo, I / Haaf, T / Hoefsloot, L / Kremer, H / Kubisch, C / Le Marechal, C / Pandya, A / Sartorato, E L / Schneider, E / Van Camp, G / Wuyts, W / Smith, R J H / Friderici, K H. ·Genetics Program, Michigan State University, East Lansing, MI 48824, USA. ·Clin Genet · Pubmed #20236118.

ABSTRACT: Eleven affected members of a large German-American family segregating recessively inherited, congenital, non-syndromic sensorineural hearing loss (SNHL) were found to be homozygous for the common 35delG mutation of GJB2, the gene encoding the gap junction protein Connexin 26. Surprisingly, four additional family members with bilateral profound SNHL carried only a single 35delG mutation. Previously, we demonstrated reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons. Using array comparative genome hybridization (array CGH), we have now identified on this allele a deletion of 131.4 kb whose proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6. This deletion, del(chr13:19,837,344-19,968,698), segregates as a completely penetrant DFNB1 allele in this family. It is not present in 528 persons with SNHL and monoallelic mutation of GJB2 or GJB6, and we have not identified any other candidate pathogenic copy number variation by arrayCGH in a subset of 10 such persons. Characterization of distant GJB2/GJB6 cis-regulatory regions evidenced by this allele may be required to find the 'missing' DFNB1 mutations that are believed to exist.

25 Article Mutations in Grxcr1 are the basis for inner ear dysfunction in the pirouette mouse. 2010

Odeh, Hana / Hunker, Kristina L / Belyantseva, Inna A / Azaiez, Hela / Avenarius, Matthew R / Zheng, Lili / Peters, Linda M / Gagnon, Leona H / Hagiwara, Nobuko / Skynner, Michael J / Brilliant, Murray H / Allen, Nicholas D / Riazuddin, Saima / Johnson, Kenneth R / Raphael, Yehoash / Najmabadi, Hossein / Friedman, Thomas B / Bartles, James R / Smith, Richard J H / Kohrman, David C. ·Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ·Am J Hum Genet · Pubmed #20137774.

ABSTRACT: Recessive mutations at the mouse pirouette (pi) locus result in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified mutations in the gene Grxcr1 (glutaredoxin cysteine-rich 1) in five independent allelic strains of pirouette mice. We also provide sequence data of GRXCR1 from humans with profound hearing loss suggesting that pirouette is a model for studying the mechanism of nonsyndromic deafness DFNB25. Grxcr1 encodes a 290 amino acid protein that contains a region of similarity to glutaredoxin proteins and a cysteine-rich region at its C terminus. Grxcr1 is expressed in sensory epithelia of the inner ear, and its encoded protein is localized along the length of stereocilia, the actin-filament-rich mechanosensory structures at the apical surface of auditory and vestibular hair cells. The precise architecture of hair cell stereocilia is essential for normal hearing. Loss of function of Grxcr1 in homozygous pirouette mice results in abnormally thin and slightly shortened stereocilia. When overexpressed in transfected cells, GRXCR1 localizes along the length of actin-filament-rich structures at the dorsal-apical surface and induces structures with greater actin filament content and/or increased lengths in a subset of cells. Our results suggest that deafness in pirouette mutants is associated with loss of GRXCR1 function in modulating actin cytoskeletal architecture in the developing stereocilia of sensory hair cells.

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