{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:04Z","timestamp":1786976824185,"version":"build-2736575974"},"reference-count":15,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002839","name":"Medical School - Charit\u00e9 - University Medicine Berlin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002839","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The clinical diagnosis criteria for CHARGE syndrome have been revised several times in the last 25\u2009years. Variable expressivity and reduced penetrance are known, particularly in mild and familial cases. Therefore, it has been proposed to include the detection of a pathogenic\n                    <jats:italic>CHD7<\/jats:italic>\n                    variant as a major diagnostic criterion. However, intronic variants not located at the canonical splice site are still underrepresented in mutation databases, often because functional analysis is not performed in the diagnostic setting. Here, we report a two\u2010generation family that did not meet the criteria for CHARGE syndrome, until the molecular findings were taken into account. By exome sequencing, we detected an intronic variant in a male individual, who presented with unilateral external ear malformation, bilateral semicircular canal aplasia, polydactyly, vertebral body fusion and a heart defect. The variant was inherited by his mother, who also had bilateral semicircular canal aplasia additionally to unilateral sensorineural hearing impairment, unilateral mandibular palpebral synkinesia, orofacial cleft, and dysphagia. Using RNA studies, we were able to demonstrate that aberrant splicing occurs at an upstream cryptic splice acceptor site, resulting in a frameshift and premature stop of translation. Our data show causality of the noncanonical intronic\n                    <jats:italic>CHD7<\/jats:italic>\n                    variant and end the diagnostic odyssey of this unsolved phenotype of the family.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63122","type":"journal-article","created":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T02:55:05Z","timestamp":1674874505000},"page":"1128-1132","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel noncanonical splice site variant causes mild\n                    <scp>\n                      <i>CHD7<\/i>\n                    <\/scp>\n                    \u2010related disorder with variable intrafamilial expressivity"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9410-9290","authenticated-orcid":false,"given":"Felix","family":"Boschann","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"},{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, BIH Biomedical Innovation Academy BIH Charit\u00e9 Clinician Scientist Program  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Kosmehl","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Helios Hospital Berlin\u2010Buch  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Bloching","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Helios Hospital Berlin\u2010Buch  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Gr\u00fcnhagen","sequence":"additional","affiliation":[{"name":"Labor Berlin Charit\u00e9 Vivantes GmbH\u2010Corporate Member of Institute for Medical Genetics and Human Genetics Charit\u00e9\u2010Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-8911","authenticated-orcid":false,"given":"Denise","family":"Horn","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Human Genetics, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Lyutenski","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Helios Hospital Berlin\u2010Buch  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.04.022"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.087106"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/000992289803700302"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61962"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37435"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa241"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31921"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.238444.118"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(81)80454-4"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.03.006"},{"key":"e_1_2_10_14_1","volume-title":"GeneReviews\u00ae [Internet]","author":"Ravenswaaij\u2010Arts C. M.","year":"2022"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30559"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1407"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63122","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.63122","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T19:05:21Z","timestamp":1692385521000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,27]]},"references-count":15,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/ajmg.a.63122"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63122","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,27]]},"assertion":[{"value":"2022-10-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}