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Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease

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Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Excess of rare missense variants in hearing loss genes in sporadic Meniere disease Alvaro Gallego-Martinez1, Teresa Requena1, Pablo Roman-Naranjo1, Jose A. Lopez-Escamez1, 2* 1Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), Spain, 2Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Spain Submitted to Journal: Frontiers in Genetics Specialty Section: Genetic Disorders Article type: Original Research Article Manuscript ID: 423463 Received on: 06 Sep 2018 Frontiers website link: Inwww.frontiersin.org review bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest Author contribution statement TR and ALE as project managers conceived the main idea of the work. Sample preparation and protocol were carry out by TR and AGM. AGM performed the bioinformatics and statistical analysis. Validations of tested SNV were done by AGM and PRN. AGM took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript. Keywords SNHL (Sensorineural hearing loss), Meniere’s disease, Vertigo, Variant aggregation test, Spanish population Abstract Word count: 200 Meniere’s disease (MD) is a clinical spectrum of rare disorders characterized by vertigo attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to medium frequencies. Although it shows familial aggregation with incomplete phenotypic forms and variable expressivity, most cases are considered sporadic. The aim of this study was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD. We conducted a targeted-sequencing study including SNHL and familial MD genes in 890 MD patients to compare the frequency of rare variants in cases using three independent public datasets as controls. Patients with sporadic MD showed a significant enrichment of missense variants in SNHL genes that was not found in the controls. The list of genes includes GJB2, USH1G, SLC26A4, ESRRB and CLDN14. A rare synonymous variant with unknown significance was found in theIn MARVELD2 gene in severalreview unrelated patients with MD. There is a burden of rare variation in certain SNHL genes in sporadic MD. Furthermore, the physical interaction of specific gene variants at protein level can explain the additive effect of rare variants in different genes in MD. This study will contribute to design a gene panel for the genetic diagnosis of MD. Funding statement Authors declare there are not any competing interests in relation to the work described. Ethics statements (Authors are required to state the ethical considerations of their study in the manuscript, including for cases where the study was exempt from ethical approval procedures) Does the study presented in the manuscript involve human or animal subjects: Yes Please provide the complete ethics statement for your manuscript. Note that the statement will be directly added to the manuscript file for peer-review, and should include the following information: Full name of the ethics committee that approved the study Consent procedure used for human participants or for animal owners Any additional considerations of the study in cases where vulnerable populations were involved, for example minors, persons with disabilities or endangered animal species As per the Frontiers authors guidelines, you are required to use the following format for statements involving human subjects: This study was carried out in accordance with the recommendations of [name of guidelines], [name of committee]. The protocol was approved by the [name of committee]. All subjects gave written informed consent in accordance with the Declaration of Helsinki. For statements involving animal subjects, please use: This study was carried out in accordance with the recommendations of 'name of guidelines, name of committee'. The protocol bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. was approved by the 'name of committee'. If the study was exempt from one or more of the above requirements, please provide a statement with the reason for the exemption(s). Ensure that your statement is phrased in a complete way, with clear and concise sentences. This study protocol was approved by the Institutional Review Board for Clinical Research (MS/2014/02), and a written informed consent to donate biological samples was obtained from all subjects in accordance with the Declaration of Helsinki. In review bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Excess of rare missense variants in hearing loss genes in sporadic 2 Meniere disease 3 4 Alvaro Gallego-Martinez1, Teresa Requena1, Pablo Roman-Naranjo1, Jose A. Lopez- 1,2* 5 Escamez for the Meniere Disease Consortium (MeDiC) 6 7 AFFILIATIONS 8 1Otology & Neurotology Group CTS 495, Department of Genomic Medicine, 9 GENYO. Centre for Genomics and Oncological Research: Pfizer / University of Granada / 10 Andalusian Regional Government, PTS Granada, Granada, Spain 11 2Department of Otolaryngology, Instituto de Investigación Biosanitaria Ibs.GRANADA, 12 Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain. 13 14 * Correspondence 15 Dr. Jose A. Lopez-Escamez 16 Otology & Neurotology Group CTS 495, Department of Genomic Medicine, GENYO. Centre 17 for Genomics and Oncological Research: Pfizer / University of Granada / Andalusian 18 Regional Government, PTS Granada 19 Avenida de la Ilustración, 114 20 18016 Granada SPAIN 21 E-mail: [email protected] 22 23 In review 1 bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 24 Abstract 25 Meniere’s disease (MD) is a clinical spectrum of rare disorders characterized by vertigo 26 attacks, associated with sensorineural hearing loss (SNHL) and tinnitus involving low to 27 medium frequencies. Although it shows familial aggregation with incomplete phenotypic 28 forms and variable expressivity, most cases are considered sporadic. The aim of this study 29 was to investigate the burden for rare variation in SNHL genes in patients with sporadic MD. 30 We conducted a targeted-sequencing study including SNHL and familial MD genes in 890 31 MD patients to compare the frequency of rare variants in cases using three independent public 32 datasets as controls. 33 Patients with sporadic MD showed a significant enrichment of missense variants in SNHL 34 genes that was not found in the controls. The list of genes includes GJB2, USH1G, SLC26A4, 35 ESRRB and CLDN14. A rare synonymous variant with unknown significance was found in 36 the MARVELD2 gene in several unrelated patients with MD. 37 There is a burden of rare variation in certain SNHL genes in sporadic MD. Furthermore, the 38 physical interaction of specific gene variants at protein level can explain the additive effect of 39 rare variants in different genes in MD. This study will contribute to design a gene panel for 40 the genetic diagnosis of MD. 41 KeywordsIn: SNHL, Meniere’s review disease, vertigo, variant aggregation, Spanish population 2 bioRxiv preprint doi: https://doi.org/10.1101/393322; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 42 Introduction 43 Meniere’s disease (MD, MIM 156000) is a chronic disorder of the inner ear 44 characterized by episodes of vertigo, associated with low to middle frequency sensorineural 45 hearing loss (SNHL), tinnitus and aural fullness (Lopez-Escamez et al. 2015). The disorder 46 produces an accumulation of endolymph in the membranous labyrinth, and it may affect both 47 ears in 25-40% of patients (termed bilateral MD) and most of cases are considered sporadic 48 (Paparella and Griebie 1984). However, heterogeneity in the phenotype is observed and some 49 patients may have co-morbid conditions such as migraine or systemic autoimmune disorders 50 (Gazquez et al. 2011; Caulley et al. 2017). This phenotypic spectrum can make the clinical 51 diagnosis challenging considering that some of the symptoms overlap with other vestibular 52 disorders such vestibular migraine (VM) or autoimmune inner ear disease (AIED) (Hietikko 53 et al. 2011; Lempert et al. 2012; Requena, Espinosa-Sanchez, and Lopez-Escamez 2014; 54 Mijovic, Zeitouni, and Colmegna 2013). 55 Epidemiological evidence showing a genetic contribution in MD is based on familial 56 aggregation studies with a high siblings recurrence risk ratio (λs= 16-48) (T.
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