{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:05:17Z","timestamp":1769151917800,"version":"3.49.0"},"reference-count":11,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T00:00:00Z","timestamp":1605225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01HG010215"],"award-info":[{"award-number":["U01HG010215"]}],"id":[{"id":"10.13039\/100000002","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":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chromodomain helicase DNA\u2010binding protein 7 (<jats:italic>CHD7<\/jats:italic>) pathogenic variants are identified in more than 90% of infants and children with CHARGE (<jats:italic>C<\/jats:italic>oloboma of the iris, retina, and\/or optic disk; congenital <jats:italic>H<\/jats:italic>eart defects, choanal <jats:italic>A<\/jats:italic>tresia, <jats:italic>R<\/jats:italic>etardation of growth and development, <jats:italic>G<\/jats:italic>enital hypoplasia, and characteristic outer and inner <jats:italic>E<\/jats:italic>ar anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, <jats:italic>CHD7<\/jats:italic> sequencing and deletion\/duplication analysis, <jats:italic>SEMA3E<\/jats:italic> sequencing, and trio exome and whole\u2010genome sequencing (WGS). We used a comprehensive clinical assessment, genome\u2010wide methylation analysis (GMA), reanalysis of WGS data, and <jats:italic>CHD7<\/jats:italic> RNA studies to discover a novel variant that causes <jats:italic>CHD7<\/jats:italic> haploinsufficiency. The 7\u2010year\u2010old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a <jats:italic>CHD7<\/jats:italic>\u2010associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of <jats:italic>CHD7<\/jats:italic> detected a novel, de novo 15 base pair deletion in Intron 4 of <jats:italic>CHD7<\/jats:italic> (c.2239\u201020_2239\u20106delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes <jats:italic>CHD7<\/jats:italic> haploinsufficiency by disrupting the canonical 3\u2032 splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel <jats:italic>CHD7<\/jats:italic> variant that causes CHARGE syndrome.<\/jats:p>","DOI":"10.1002\/ajmg.a.61962","type":"journal-article","created":{"date-parts":[[2020,11,13]],"date-time":"2020-11-13T08:59:56Z","timestamp":1605257996000},"page":"544-548","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Discovery of a novel <scp><i>CHD7<\/i> CHARGE<\/scp> syndrome variant by integrated omics analyses"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4243-204X","authenticated-orcid":false,"given":"Jorge L.","family":"Granadillo","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Wegner","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander J.","family":"Paul","sequence":"additional","affiliation":[{"name":"McDonnell Genome Institute, Washington University School of Medicine  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia","family":"Willing","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Sisco","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew L.","family":"Tedder","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6363-0016","authenticated-orcid":false,"given":"Bekim","family":"Sadikovic","sequence":"additional","affiliation":[{"name":"Molecular Diagnostics Division Pathology and Laboratory Medicine. London Health Sciences Centre and St. Joseph's Health Care  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer A.","family":"Wambach","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6027-6020","authenticated-orcid":false,"given":"Dustin","family":"Baldridge","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francis Sessions","family":"Cole","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine, Saint Louis Children's Hospital  Saint Louis Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,11,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20010301)99:2<124::aid-ajmg1114>3.0.co;2-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.10.044"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.12.008"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2015.05.009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.087106"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/000992289803700302"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.036061"},{"key":"e_1_2_9_9_1","volume-title":"GeneReviews(\u00ae)","author":"Lalani S. R.","year":"1993"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.017640"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30559"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"}],"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.61962","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.61962","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.61962","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T01:23:49Z","timestamp":1692235429000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.61962"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,13]]},"references-count":11,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["10.1002\/ajmg.a.61962"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.61962","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,13]]},"assertion":[{"value":"2020-09-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}