{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T09:08:05Z","timestamp":1778836085029,"version":"3.51.4"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100013365","name":"West China Hospital, Sichuan University","doi-asserted-by":"publisher","award":["ZYJC20002"],"award-info":[{"award-number":["ZYJC20002"]}],"id":[{"id":"10.13039\/501100013365","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>MYO7A<\/jats:italic>\n                    is a causal gene, underlying Usher syndrome type 1B (USH1B) and both autosomal recessive (DFNB2) and dominant (DFNA11) non\u2010syndromic hearing loss. Despite the large number of reported\n                    <jats:italic>MYO7A<\/jats:italic>\n                    variants (over 2,200), variants located in an extended splice region remain difficult to interpret and are often classified as variants of uncertain significance (VUS). We investigated the clinical impact of\n                    <jats:italic>MYO7A<\/jats:italic>\n                    extended splice region variants, located within \u00b150\u2009bp of exon\u2013intron boundaries, by analyzing a nationwide Chinese cohort of 10,664 undiagnosed individuals with hearing loss. Twelve such variants (in 11 probands, two variants were in\n                    <jats:italic>cis<\/jats:italic>\n                    ) were identified for functional analysis. Using minigene splicing assays coupled with\n                    <jats:italic>in silico<\/jats:italic>\n                    splicing predictions, we evaluated each variant's effect on pre\u2010mRNA processing and applied ACMG\/AMP guidelines for classification. Six of the tested variants completely disrupted normal splicing, and eight variants in total were reclassified from VUS to pathogenic or likely pathogenic based on aberrant transcript outcomes. Notably, several variants generated multiple distinct abnormal transcripts, and two\u2010thirds of these variants fell within the myosin motor domain (others in the FERM2 domain). Splicing predictions from\n                    <jats:italic>in silico<\/jats:italic>\n                    algorithms were largely concordant with the experimental results, further supporting their utility in variant interpretation. This functional evidence enabled definitive molecular diagnoses in previously unresolved cases spanning DFNA11, DFNB2, and USH1B phenotypes. In summary, our study demonstrated that integrating experimental splicing assays with predictive tools can definitively determine the pathogenicity of extended splice region variants in\n                    <jats:italic>MYO7A<\/jats:italic>\n                    , thereby improving the diagnostic accuracy of genetic testing for both non\u2010syndromic and syndromic hearing loss. This approach could be applied to other genes to enhance genetic diagnosis. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70048","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:35:31Z","timestamp":1773909331000},"page":"222-231","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional reassessment of extended splice region variants in\n                    <scp>\n                      <i>MYO7A<\/i>\n                    <\/scp>\n                    with hearing loss and Usher syndrome"],"prefix":"10.1002","volume":"269","author":[{"given":"Tao","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology \u2013 Head and Neck Surgery Peking University People's Hospital  Beijing PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, West China Hospital, West China Medical School Sichuan University  Chengdu PR China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University  Chengdu PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohuan","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University  Chengdu PR China"},{"name":"Genomics Center, Core Facility of West China Hospital Sichuan University  Chengdu PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology \u2013 Head and Neck Surgery Peking University People's Hospital  Beijing PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9530-0468","authenticated-orcid":false,"given":"Yixin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology \u2013 Head and Neck Surgery Peking University People's Hospital  Beijing PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, West China Hospital, West China Medical School Sichuan University  Chengdu PR China"},{"name":"Institute of Rare Diseases, West China Hospital of Sichuan University  Chengdu PR China"},{"name":"Genomics Center, Core Facility of West China Hospital Sichuan University  Chengdu PR China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/374060a0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-022-02448-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-268"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0697-188"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0697-191"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/AUD.0000000000001066"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901819106"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2414707122"},{"key":"e_1_2_8_10_1","unstructured":"BjbK LentzJ.Usher Syndrome Type I: GeneReviews\u2122 2016. 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