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Hearing Disorders: HELP
Articles by Diana L. Kolbe
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, D. Kolbe wrote the following 12 articles about Hearing Disorders.
 
+ Citations + Abstracts
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 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.

3 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.

4 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.

5 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.

6 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.

7 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.

8 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.

9 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.

10 Article Copy number variants are a common cause of non-syndromic hearing loss. 2014

Shearer, A Eliot / Kolbe, Diana L / Azaiez, Hela / Sloan, Christina M / Frees, Kathy L / Weaver, Amy E / Clark, Erika T / Nishimura, Carla J / Black-Ziegelbein, E Ann / Smith, Richard J H. ·Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA. · Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. · Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA ; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa 52242, USA. ·Genome Med · Pubmed #24963352.

ABSTRACT: BACKGROUND: Copy number variants (CNVs) are a well-recognized cause of genetic disease; however, methods for their identification are often gene-specific, excluded as 'routine' in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. We aimed to incorporate a method for CNV identification as part of our standard analysis pipeline and to determine the contribution of CNVs to genetic hearing loss. METHODS: We used targeted genomic enrichment and massively parallel sequencing to isolate and sequence all exons of all genes known to cause NSHL. We completed testing on 686 patients with hearing loss with no exclusions based on type of hearing loss or any other clinical features. For analysis we used an integrated method for detection of single nucleotide changes, indels and CNVs. CNVs were identified using a previously published method that utilizes median read-depth ratios and a sliding-window approach. RESULTS: Of 686 patients tested, 15.2% (104) carried at least one CNV within a known deafness gene. Of the 38.9% (267) of individuals for whom we were able to determine a genetic cause of hearing loss, a CNV was implicated in 18.7% (50). We identified CNVs in 16 different genes including 7 genes for which no CNVs have been previously reported. CNVs of STRC were most common (73% of CNVs identified) followed by CNVs of OTOA (13% of CNVs identified). CONCLUSION: CNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.

11 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.

12 Minor Targeted genomic enrichment and massively parallel sequencing identifies novel nonsyndromic hearing impairment pathogenic variants in Cameroonian families. 2016

Lebeko, K / Sloan-Heggen, C M / Noubiap, J J N / Dandara, C / Kolbe, D L / Ephraim, S S / Booth, K T / Azaiez, H / Santos-Cortez, R L P / Leal, S M / Smith, R J H / Wonkam, A. ·Division of Human Genetics, Department of Pathology, Faculty of Health Sciences University of Cape Town, Cape Town, South Africa. · Department of Otolaryngology, Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, USA. · Department of Medicine, Faculty of Health Sciences University of Cape Town, Cape Town, South Africa. · Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. ·Clin Genet · Pubmed #27246798.

ABSTRACT: In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE®) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa.