{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:07:46Z","timestamp":1780582066021,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T00:00:00Z","timestamp":1637107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Audiology Research"],"abstract":"<jats:p>Hearing loss (HL) is one of the most common sensory impairments worldwide and represents a critical medical and public health issue. Since the mid-1900s, great efforts have been aimed at understanding the etiology of both syndromic and non-syndromic HL and identifying correlations with specific audiological phenotypes. The extraordinary discoveries in the field of molecular genetics during the last three decades have contributed substantially to the current knowledge. Next-generation sequencing technologies have dramatically increased the diagnostic rate for genetic HL, enabling the detection of novel variants in known deafness-related genes and the discovery of new genes implicated in hearing disease. Overall, genetic factors account for at least 40% of the cases with HL, but a portion of affected patients still lack a definite molecular diagnosis. Important steps forward have been made, but many aspects still have to be clarified. In particular, the role of epigenetics in the development, function and pathology of hearing is a research field that still needs to be explored. This research is extremely challenging due to the time- and tissue-dependent variability of the epigenetic changes. Multisystem diseases are expected to be investigated at first: specific epi-signatures have been identified for several syndromic disorders and represent potential markers for molecular diagnostics.<\/jats:p>","DOI":"10.3390\/audiolres11040057","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T09:16:11Z","timestamp":1637140571000},"page":"629-635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genetics &amp; Epigenetics of Hereditary Deafness: An Historical Overview"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2003-6348","authenticated-orcid":false,"given":"Alessandro","family":"Martini","sequence":"first","affiliation":[{"name":"Padova University Research Center \u201cInternational Auditory Processing Project in Venice (I-APPROVE)\u201d, \u201cSanti Giovanni e Paolo\u201d Hospital, 30122 Venice, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Otolaryngology Unit, Department of Neurosciences, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8139-6198","authenticated-orcid":false,"given":"Ugo","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0270-1698","authenticated-orcid":false,"given":"Matteo","family":"Cassina","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Women\u2019s and Children\u2019s Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening\u2014A silent revolution","volume":"354","author":"Morton","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1038\/s41436-019-0563-5","article-title":"A proposal for comprehensive newborn hearing screening to improve identification of deaf and hard-of-hearing children","volume":"21","author":"Shearer","year":"2019","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Usami, S.-I., and Nishio, S.-Y. (2021). The genetic etiology of hearing loss in Japan revealed by the social health insurance-based genetic testing of 10K patients. Qual. Life Res., 1\u201317.","DOI":"10.1007\/s00439-021-02371-3"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1017\/S0022215100050969","article-title":"The Aetiology of Congenital Deafness and Audiometric Patterns","volume":"69","author":"Fisch","year":"1955","journal-title":"J. Laryngol. Otol."},{"key":"ref_5","unstructured":"Wolstenholme, G.E.W., and Knight, J. (1970). The causes of profound deafness in childhood. Sensorineural Hearing Loss, J. & A. Churchill."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/00206097109072563","article-title":"Genetic counseling for the hearing impaired","volume":"10","author":"Nance","year":"1971","journal-title":"Int. J. Audiol."},{"key":"ref_7","first-page":"2","article-title":"Syndromal approaches to the nosology of hereditary deafness","volume":"7","author":"Konigsmark","year":"1971","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_8","unstructured":"Konigsmark, B.W., and Gorlin, R.J. (1976). Genetic and Metabolic Deafness, W. B. Saunders Company."},{"key":"ref_9","unstructured":"Gorlin, R.J., Toriello, H.V., and Cohen, M.M. (1995). Hereditary Hearing Loss and Its Syndromes, Oxford University Press. Oxford Monographs on Medical Genetics No. 28."},{"key":"ref_10","unstructured":"Toriello, H.V., and Smith, S.D. (2013). Hereditary Hearing Loss and Its Syndromes, Oxford University Press. [3rd ed.]. Oxford Monographs on Medical Genetics."},{"key":"ref_11","unstructured":"McKusick, V.A. (1992). Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes, Johns Hopkins University Press."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"McKusick, V.A. (1998). Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders, Johns Hopkins University Press.","DOI":"10.56021\/9780801857423"},{"key":"ref_13","unstructured":"Online Mendelian Inheritance in Man, OMIM\u00ae (2021, November 11). McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University: Baltimore, MD, USA. Available online: http:\/\/omim.org."},{"key":"ref_14","first-page":"337","article-title":"The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK","volume":"80","author":"Brunner","year":"1988","journal-title":"Qual. Life Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0888-7543(88)90119-X","article-title":"X-linked mixed deafness with stapes fixation in a Mauritian kindred: Linkage to Xq probe pDP34","volume":"3","author":"Wallis","year":"1988","journal-title":"Genomics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1126\/science.7839145","article-title":"Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4","volume":"267","author":"Huber","year":"1995","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5181","DOI":"10.1073\/pnas.89.11.5181","article-title":"The gene for an inherited form of deafness maps to chromosome 5q31","volume":"89","author":"Leon","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1126\/science.278.5341.1315","article-title":"Nonsyndromic Deafness DFNA1 Associated with Mutation of a Human Homolog of the Drosophila Gene diaphanous","volume":"278","author":"Lynch","year":"1997","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng0194-24","article-title":"A non\u2013syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q","volume":"6","author":"Guilford","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_20","first-page":"80","article-title":"Connexin 26 mutations in hereditary non-syndromic sensorineural deafness","volume":"387","author":"Kelsell","year":"1997","journal-title":"Nat. Cell Biol."},{"key":"ref_21","unstructured":"Martini, A., Read, A., and Stephens, D. (1996). Genetics and Hearing Impairments, Whurr."},{"key":"ref_22","unstructured":"Stephens, D., Read, A., and Martini, A. (1998). Developments in Genetic Hearing Impairment, Whurr."},{"key":"ref_23","unstructured":"Martini, A., Mazzoli, M., Read, A., and Stephens, D. (2001). Definitions and Guidelines in Genetic Hearing Impairment, Whurr."},{"key":"ref_24","unstructured":"Stephens, D., and Jones, L. (2005). The Impact of Genetic Hearing Impairment, Whurr."},{"key":"ref_25","unstructured":"Stephens, D., and Jones, L. (2006). The Effect of Genetic Hearing Impairment in the Family, Whurr."},{"key":"ref_26","unstructured":"Van Camp, G., and Smith, R.J.H. (2021, September 14). Hereditary Hearing Loss Homepage. Available online: https:\/\/hereditaryhearingloss.org."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1080\/21695717.2020.1807260","article-title":"Molecular testing for the study of non-syndromic hearing loss","volume":"18","author":"Morgan","year":"2020","journal-title":"Hear. Balance Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.ajhg.2018.08.006","article-title":"Genomic Landscape and Mutational Signatures of Deafness-Associated Genes","volume":"103","author":"Azaiez","year":"2018","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.heares.2019.01.003","article-title":"Hereditary hearing loss; about the known and the unknown","volume":"376","author":"Kremer","year":"2019","journal-title":"Hear. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.tig.2018.05.008","article-title":"The Third Revolution in Sequencing Technology","volume":"34","author":"Jaszczyszyn","year":"2018","journal-title":"Trends Genet."},{"key":"ref_32","first-page":"18","article-title":"The epigenotype","volume":"1","author":"Waddington","year":"1942","journal-title":"Endeavour"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1055\/s-0029-1237423","article-title":"Epigenetics: Definition, Mechanisms and Clinical Perspective","volume":"27","author":"Dupont","year":"2009","journal-title":"Semin. Reprod. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1073\/pnas.44.7.712","article-title":"Epigenetic Control Systems","volume":"44","author":"Nanney","year":"1958","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/171737a0","article-title":"Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid","volume":"171","author":"Watson","year":"1953","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1534\/genetics.114.173492","article-title":"What do you mean, \u201cepigenetic\u201d?","volume":"199","author":"Deans","year":"2015","journal-title":"Genetics"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Waddington, C.H. (1956). Principles of Embryology, Macmillan Co.","DOI":"10.5962\/bhl.title.7217"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"A160","DOI":"10.1289\/ehp.114-a160","article-title":"Epigenetics: The science of change","volume":"114","author":"Weinhold","year":"2006","journal-title":"Environ. Health Perspect"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3389\/fncel.2014.00446","article-title":"Epigenetic regulation in the inner ear and its potential roles in development, protection, and regeneration","volume":"8","author":"Layman","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.heares.2007.07.002","article-title":"A role for epigenetics in hearing: Establishment and maintenance of auditory specific gene expression patterns","volume":"233","author":"Provenzano","year":"2007","journal-title":"Hear. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.semcdb.2016.11.002","article-title":"Insights into inner ear-specific gene regulation: Epigenetics and non-coding RNAs in inner ear development and regeneration","volume":"65","author":"Doetzlhofer","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)31561-0","article-title":"Sex and gender: Modifiers of health, disease, and medicine","volume":"396","author":"Barnes","year":"2020","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/21695717.2019.1615812","article-title":"Gender-related hearing, balance and speech disorders: A review","volume":"17","author":"Zanon","year":"2019","journal-title":"Hear. Balance Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1080\/21695717.2019.1663041","article-title":"From Mondini to the latest inner ear malformations\u2019 classifications: An historical and critical review","volume":"17","author":"Brotto","year":"2019","journal-title":"Hear. Balance Commun."},{"key":"ref_45","first-page":"89","article-title":"Cell--cell interaction as an epigenetic determinant in the expression of mutant neural crest cells","volume":"15","author":"Riccardi","year":"1979","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_46","first-page":"201","article-title":"Monozygotic twins discordant for the oculo-oto-radial syndrome (IVIC syndrome)","volume":"8","author":"Berry","year":"1997","journal-title":"Genet. Couns."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"144996","DOI":"10.1016\/j.gene.2020.144996","article-title":"Recent advancements in understanding the role of epi-genetics in the auditory system","volume":"761","author":"Mittal","year":"2020","journal-title":"Gene"},{"key":"ref_48","first-page":"1","article-title":"DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium","volume":"8","author":"Valensisi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/j.ajhg.2021.06.015","article-title":"Anatomy of DNA methylation signatures: Emerging insights and applications","volume":"108","author":"Goodman","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_50","first-page":"1","article-title":"BAFopathies\u2019 DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin\u2013Siris and Nicolaides\u2013Baraitser syndromes","volume":"9","author":"Bend","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Audiology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4349\/11\/4\/57\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:31:27Z","timestamp":1760167887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4349\/11\/4\/57"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,17]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["audiolres11040057"],"URL":"https:\/\/doi.org\/10.3390\/audiolres11040057","relation":{},"ISSN":["2039-4349"],"issn-type":[{"value":"2039-4349","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,17]]}}}