{
    "abstract": "M\u00e9ni\u00e8re's disease (MD) is a disorder of the inner ear that causes episodic bouts of severe dizziness, roaring tinnitus, and fluctuating hearing loss. To date, no targeted therapy exists. As such, we have undertaken a large whole genome sequencing study on carefully phenotyped unilateral MD patients with the goal of gene/pathway discovery and a move towards targeted intervention. This study was a retrospective review of patients with a history of M\u00e9ni\u00e8re's disease. Genomic DNA, acquired from saliva samples, was purified and subjected to whole genome sequencing.\nStringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.\nBy enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.",
    "authors": [
        {
            "affiliation": "Center for Computational Biology & Bioinformatics, University of California, San Diego, La Jolla, CA, USA. kfisch@health.ucsd.edu.\nDepartment of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA. kfisch@health.ucsd.edu.",
            "firstname": "Kathleen M",
            "initials": "KM",
            "lastname": "Fisch"
        },
        {
            "affiliation": "Center for Computational Biology & Bioinformatics, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Sara Brin",
            "initials": "SB",
            "lastname": "Rosenthal"
        },
        {
            "affiliation": "Center for Computational Biology & Bioinformatics, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Adam",
            "initials": "A",
            "lastname": "Mark"
        },
        {
            "affiliation": "Center for Computational Biology & Bioinformatics, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Roman",
            "initials": "R",
            "lastname": "Sasik"
        },
        {
            "affiliation": "Center for Computational Biology & Bioinformatics, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Chanond A",
            "initials": "CA",
            "lastname": "Nasamran"
        },
        {
            "affiliation": "Department of Otolaryngology, Head & Neck Surgery, University of California, San Diego, La Jolla, CA, USA.\nResearch Department, VA Hospitals, San Diego, CA, USA.",
            "firstname": "Royce",
            "initials": "R",
            "lastname": "Clifford"
        },
        {
            "affiliation": "House Institute Foundation, Los Angeles, CA, USA.",
            "firstname": "M Jennifer",
            "initials": "MJ",
            "lastname": "Derebery"
        },
        {
            "affiliation": "Department of Otolaryngology, Head & Neck Surgery, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Ely",
            "initials": "E",
            "lastname": "Boussaty"
        },
        {
            "affiliation": "Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Kristen",
            "initials": "K",
            "lastname": "Jepsen"
        },
        {
            "affiliation": "Department of Otolaryngology, Head & Neck Surgery, University of California, San Diego, La Jolla, CA, USA.",
            "firstname": "Jeffrey",
            "initials": "J",
            "lastname": "Harris"
        },
        {
            "affiliation": "Department of Otolaryngology, Head & Neck Surgery, University of California, San Diego, La Jolla, CA, USA. rafriedman@health.ucsd.edu.",
            "firstname": "Rick A",
            "initials": "RA",
            "lastname": "Friedman"
        }
    ],
    "conclusions": "By enabling the development of model systems that may lead to targeted therapies and MD screening panels, the genes and variants identified in this study will inform diagnosis and treatment of MD.",
    "copyrights": "\u00a9 2024. The Author(s).",
    "doi": "10.1186/s12864-024-10552-3\n10.1016/j.otc.2010.05.001\n10.3233/VES-150549\n10.1080/08869634.2003.11746242\n10.1177/000348940911800603\n10.1097/00129492-200111000-00030\n10.1017/S0022215108002788\n10.1002/ajmg.b.30347\n10.1038/jhg.2010.122\n10.1097/MAO.0b013e3182868818\n10.1097/MAO.0b013e318180a4b1\n10.1111/j.1365-2826.2010.02060.x\n10.1159/000322346\n10.1038/nature15393\n10.1007/s10592-018-1072-9\n10.1073/pnas.1912156116\n10.1016/j.heares.2011.12.003\n10.1038/s12276-020-0377-1\n10.1186/1478-811X-10-20\n10.1093/biostatistics/kxs014\n10.1038/nrg.2017.38\n10.1007/978-1-4939-6427-7_3\n10.1016/j.ajhg.2012.09.011\n10.1038/70516\n10.1681/ASN.2012100985\n10.1007/978-3-030-38062-5_13\n10.1002/(SICI)1096-8628(19990924)89:3<147::AID-AJMG5>3.0.CO;2-6\n10.1016/j.ebiom.2021.103309\n10.1038/s41436-019-0487-0\n10.15252/embr.201643689\n10.1038/s41431-021-00913-x\n10.1016/j.celrep.2023.112623\n10.1073/pnas.2221744120\n10.1016/j.ajhg.2024.01.008\n10.1097/00006842-195303000-00003\n10.1242/jcs.261100\n10.1172/jci.insight.128561\n10.1038/s42003-021-02673-2\n10.1038/s41598-021-01876-1\n10.1007/s00415-015-7988-9\n10.1038/ng.806\n10.1093/nar/gku1003\n10.1093/nar/gkz369",
    "journal": "BMC genomics",
    "keywords": [
        "Gene discovery",
        "M\u00e9ni\u00e8re's disease",
        "Network analysis",
        "Systems biology",
        "Whole genome sequencing"
    ],
    "methods": null,
    "publication_date": "2024-06-29",
    "pubmed_id": "38943082\n13836950\n20713236\n25882471\n12723860\n19663372\n11698814\n8109627\n18616841\n16741942\n20927121\n23598705\n18667944\n20722976\n21063116\n26432245\n30100824\n31636190\n22200607\n31988333\n22788415\n22699862\n28607512\n27933520\n23122586\n16385458\n10581026\n24052634\n32451864\n10704189\n33813136\n30894701\n28893864\n34135477\n36933008\n37289589\n37339214\n38330941\n26545070\n13037944\n37096733\n31217345\n34620984\n34795337\n27083884\n26343803\n21478889\n25352553\n31066453",
    "results": "Stringent variant calling, performed on 511 samples passing quality checks, followed by gene-based filtering by recurrence and proximity in molecular interaction networks, led to 481 high priority MD genes. These high priority genes, including MPHOSPH8, MYO18A, TRIOBP, OTOGL, TNC, and MYO6, were previously implicated in hearing loss, balance, and cochlear function, and were significantly enriched in common variant studies of hearing loss. Validation in an independent MD cohort confirmed 82 recurrent genes. Pathway analysis pointed to cell-cell adhesion, extracellular matrix, and cellular energy maintenance as key mediators of MD. Furthermore, the MD-prioritized genes were highly expressed in human inner ear hair cells and dark/vestibular cells, and were differentially expressed in a mouse model of hearing loss.",
    "title": "The genomic landscape of M\u00e9ni\u00e8re's disease: a path to endolymphatic hydrops.",
    "xml": "<Element 'PubmedArticle' at 0x788505616fc0>"
}