{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:37:34Z","timestamp":1780540654200,"version":"3.54.1"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T00:00:00Z","timestamp":1736121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["20FC1048"],"award-info":[{"award-number":["20FC1048"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["23FC0201"],"award-info":[{"award-number":["23FC0201"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP16kk0205010"],"award-info":[{"award-number":["JP16kk0205010"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP18ek0109363"],"award-info":[{"award-number":["JP18ek0109363"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP19dk0310097"],"award-info":[{"award-number":["JP19dk0310097"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP19kk0205023"],"award-info":[{"award-number":["JP19kk0205023"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP21ek0109542"],"award-info":[{"award-number":["JP21ek0109542"]}]},{"name":"Health and Labor Sciences Research Grant for Research on Rare and Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan","award":["JP24ek0109741"],"award-info":[{"award-number":["JP24ek0109741"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["20FC1048"],"award-info":[{"award-number":["20FC1048"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["23FC0201"],"award-info":[{"award-number":["23FC0201"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP16kk0205010"],"award-info":[{"award-number":["JP16kk0205010"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP18ek0109363"],"award-info":[{"award-number":["JP18ek0109363"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP19dk0310097"],"award-info":[{"award-number":["JP19dk0310097"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP19kk0205023"],"award-info":[{"award-number":["JP19kk0205023"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP21ek0109542"],"award-info":[{"award-number":["JP21ek0109542"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP24ek0109741"],"award-info":[{"award-number":["JP24ek0109741"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: A heterozygous mutation in the WFS1 gene is responsible for autosomal dominant non-syndromic hearing loss (DFNA6\/14\/38) and Wolfram-like syndrome, which is characterized by bilateral sensorineural hearing loss with optic atrophy and\/or diabetes mellitus. However, detailed clinical features for the patients with the heterozygous p.A684V variant remain unknown. Methods: We report the clinical details of 14 cases with a heterozygous p.A684V variant in the WFS1 gene identified from target resequencing analysis of 63 previously reported deafness genes by next-generation sequencing of 15,684 hearing loss patients (mean age 27.5 \u00b1 23.1 years old, 6574 male, 8612 female and 498 for whom information was unavailable). Results: Among the 14 patients from 13 families with the p.A684V variant, nine were sporadic cases. In addition, we confirmed de novo occurrence of this variant in seven families. This result strongly supports the notion that this variant was located on a mutational hotspot. When comparing previously reported cases of autosomal dominant WFS1 gene-associated hearing loss, most of the patients in this study showed severe-to-profound bilateral sensorineural hearing loss (genotype\u2013phenotype correlation). Two patients had optic atrophy, while the others did not have any other complications. Conclusions: The identified heterozygous p.A684V variant appears to be a hotspot mutation and likely to cause severe-to-profound hearing loss in early childhood. Cochlear implantation is considered favorable in cases of hearing impairment due to this variant.<\/jats:p>","DOI":"10.3390\/genes16010057","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T09:17:02Z","timestamp":1736155022000},"page":"57","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Heterozygous p.A684V Variant in the WFS1 Gene Is a Mutational Hotspot Causing a Severe Hearing Loss Phenotype"],"prefix":"10.3390","volume":"16","author":[{"given":"Shintaro","family":"Otsuka","sequence":"first","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6640-2297","authenticated-orcid":false,"given":"Shin-ya","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-9751","authenticated-orcid":false,"given":"Shinya","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Hokkaido University, Sapporo 060-8648, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Fukushima Medical University, Fukushima 960-1295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, International University of Health and Welfare Mita Hospital, Tokyo 108-8329, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kozo","family":"Kumakawa","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Akasaka Toranomon Clinic, Tokyo 107-0052, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Head & Neck Surgery, Kitasao University, Sagamihara 252-0375, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9601-7496","authenticated-orcid":false,"given":"Hidekane","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology-Head and Neck Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8924-0710","authenticated-orcid":false,"given":"Norio","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Kobe City Medical Center General Hospital, Kobe 650-0047, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, University of the Ryukyus, Okinawa 903-0215, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9169-9707","authenticated-orcid":false,"given":"Mari","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomo","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Kitahara","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-6122","authenticated-orcid":false,"given":"Shin-ichi","family":"Usami","sequence":"additional","affiliation":[{"name":"Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/hmg\/10.5.477","article-title":"WFS1 (Wolfram syndrome 1) gene product: Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain","volume":"10","author":"Takeda","year":"2001","journal-title":"Hum. 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