{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:20Z","timestamp":1788544160687,"version":"build-2803163510"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Indiana University Pervasive Technology Institute"},{"name":"Lilly Endowment, Inc."},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL 134599"],"award-info":[{"award-number":["P01 HL 134599"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left\u2013right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and\/or reduced length and number of motile cilia, affecting the establishment of the left\u2013right axis. In humans, heterozygous pathogenic variants in FOXJ1 cause ciliopathy leading to situs inversus, obstructive hydrocephalus and chronic airway disease. Here, we report a novel truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs*12) identified by clinical exome sequencing from a patient with isolated congenital heart defects (CHD) which included atrial and ventricular septal defects, double outlet right ventricle (DORV) and transposition of the great arteries. Functional experiments show that FOXJ1 c.784_799dup; p.Glu267Glyfs*12, unlike FOXJ1, fails to induce ectopic cilia in frog epidermis in vivo or to activate the ADGB promoter, a downstream target of FOXJ1 in cilia, in transactivation assays in vitro. Variant analysis of patients with heterotaxy or heterotaxy-related CHD indicates that pathogenic variants in FOXJ1 are an infrequent cause of heterotaxy. Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice, demonstrating randomized heart looping. Abnormal heart looping includes reversed looping (dextrocardia), ventral looping and no looping\/single ventricle hearts. Complex CHDs revealed by histological analysis include atrioventricular septal defects, DORV, single ventricle defects as well as abnormal position of the great arteries. These results indicate that pathogenic variants in FOXJ1 can cause isolated CHD.<\/jats:p>","DOI":"10.1093\/hmg\/ddad065","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T23:56:57Z","timestamp":1683763017000},"page":"2335-2346","source":"Crossref","is-referenced-by-count":18,"title":["Congenital heart defects caused by <i>FOXJ1<\/i>"],"prefix":"10.1093","volume":"32","author":[{"given":"Maria B","family":"Padua","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M","family":"Helm","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"},{"name":"Department of Epidemiology, Indiana University Fairbanks School of Public Health , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Wells","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M","family":"Bellchambers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthi","family":"Sridhar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"},{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, IN 46202 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"issue":"21","key":"2023070515080256700_ref1","doi-asserted-by":"crossref","first-page":"e653","DOI":"10.1161\/CIR.0000000000000606","article-title":"Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association","volume":"138","author":"Pierpont","year":"2018","journal-title":"Circulation"},{"issue":"10","key":"2023070515080256700_ref2","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1161\/CIRCRESAHA.115.304458","article-title":"Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data","volume":"115","author":"Glessner","year":"2014","journal-title":"Circ. 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