{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:03:37Z","timestamp":1789358617412,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the\n                    <jats:italic>CHD7<\/jats:italic>\n                    gene. Most pathogenic\n                    <jats:italic>CHD7<\/jats:italic>\n                    variants are loss\u2010of\u2010function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous\n                    <jats:italic>CHD7<\/jats:italic>\n                    variant (NM_017780.4:c.5273A&gt;G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript\u2010level consequences remain unclear. Long\u2010PCR\u2013based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28\u2010bp deletion due to cryptic donor splice\u2010site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A&gt;G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA\u2010level splicing analysis for the accurate interpretation and classification of\n                    <jats:italic>CHD7<\/jats:italic>\n                    missense variants.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70302","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T03:22:18Z","timestamp":1789356138000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Aberrant Splicing Caused by an Apparently Missense\n                    <scp>\n                      <i>CHD7<\/i>\n                    <\/scp>\n                    Variant,\n                    <scp>c.5273A&gt;G<\/scp>\n                    (\n                    <scp>p.Asp1758Gly<\/scp>\n                    ), in\n                    <scp>CHARGE<\/scp>\n                    Syndrome"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8607-1437","authenticated-orcid":false,"given":"Takashi","family":"Okuno","sequence":"first","affiliation":[{"name":"Department of Pediatrics Faculty of Medical Sciences, University of Fukui  Fukui Japan"},{"name":"Department of Medical Genetics University of Fukui Hospital  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuto","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Faculty of Medical Sciences, University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1786-592X","authenticated-orcid":false,"given":"Aiko","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Faculty of Medical Sciences, University of Fukui  Fukui Japan"},{"name":"Department of Medical Genetics University of Fukui Hospital  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumi","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of Fukui Hospital  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9785-0535","authenticated-orcid":false,"given":"Masamichi","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of Fukui Hospital  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3189-8111","authenticated-orcid":false,"given":"Sumihito","family":"Togi","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine Medical Research Institute, Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7600-3481","authenticated-orcid":false,"given":"Hiroki","family":"Ura","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine Medical Research Institute, Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-7962","authenticated-orcid":false,"given":"Yo","family":"Niida","sequence":"additional","affiliation":[{"name":"Center for Clinical Genomics Kanazawa Medical University Hospital  Uchinada Ishikawa Japan"},{"name":"Division of Genomic Medicine, Department of Advanced Medicine Medical Research Institute, Kanazawa Medical University  Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6844-2011","authenticated-orcid":false,"given":"Katsutsugu","family":"Umeda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Faculty of Medical Sciences, University of Fukui  Fukui Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13353\u2010018\u20100444\u20107"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg215"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.087106"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-1-34","article-title":"CHARGE Syndrome","volume":"1","author":"Blake K. 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