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The first reports describing a <jats:italic>TSPEAR<\/jats:italic> disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype\u2013phenotype associations for <jats:italic>TSPEAR<\/jats:italic> variants, we characterized 13 individuals with biallelic <jats:italic>TSPEAR<\/jats:italic> variants. Individuals underwent either exome sequencing or panel\u2010based genetic testing. Nearly all of these newly reported individuals (11\/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing\u2010loss\u2010associated genes, specifically <jats:italic>TMPRSS3<\/jats:italic>, <jats:italic>GJB2<\/jats:italic>, and <jats:italic>GJB6<\/jats:italic>, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of <jats:italic>TSPEAR<\/jats:italic> variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether <jats:italic>TSPEAR<\/jats:italic> variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.<\/jats:p>","DOI":"10.1002\/ajmg.a.62347","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T11:30:02Z","timestamp":1622115002000},"page":"2417-2433","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["<scp><i>TSPEAR<\/i><\/scp> variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9468-3284","authenticated-orcid":false,"given":"Bradley","family":"Bowles","sequence":"first","affiliation":[{"name":"Center for Individualized Medicine, Mayo Clinic  Rochester Minnesota 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