{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T21:57:55Z","timestamp":1757541475661,"version":"3.40.5"},"reference-count":8,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Heterozygous missense variants in <jats:italic>TGFBR1<\/jats:italic>, encoding one subunit of the transforming growth factor\u2010beta receptor, are a well\u2010established cause of Loeys\u2010Dietz syndrome (LDS)\u2014an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life\u2010threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of <jats:italic>TGFBR1<\/jats:italic>\u2010related disease. Each born at 38\u2009weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66\u2009days of age and Patient 2 is alive at 4\u2009years and 4\u2009months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF\u2010\u03b2 responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of <jats:italic>TGFBR1<\/jats:italic> (c.239G&gt;A; p.Arg80Gln paternal and c.313C&gt;G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS\u2014an established autosomal dominant disease. These siblings represent the first reports of biallelic <jats:italic>TGFBR1<\/jats:italic>\u2010related LDS and expand the differential diagnosis of CDH.<\/jats:p>","DOI":"10.1002\/ajmg.a.63075","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T20:59:15Z","timestamp":1672433955000},"page":"786-793","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Siblings with profound connective tissue disease: First report of biallelic <scp><i>TGFBR1<\/i><\/scp>\u2010related <scp>Loeys\u2010Dietz<\/scp> syndrome"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9212-2499","authenticated-orcid":false,"given":"Lois Janelle","family":"Starr","sequence":"first","affiliation":[{"name":"Department of Pediatrics Munroe\u2010Meyer Institute, University of Nebraska Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark Evan","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Pediatric Cardiology, Department of Pediatrics Mass General for Children, Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Cardiology, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Cardiovascular Research Center, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian lacks","family":"Lino Cardenas","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Department of Medicine Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anji T.","family":"Yetman","sequence":"additional","affiliation":[{"name":"Division of Cardiology Children's Hospital and Medical Center  Omaha Nebraska USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1002\/ajmg.a.61844"},{"doi-asserted-by":"publisher","key":"e_1_2_9_3_1","DOI":"10.1002\/ajmg.a.36960"},{"doi-asserted-by":"publisher","key":"e_1_2_9_4_1","DOI":"10.3109\/10799893.2012.664553"},{"doi-asserted-by":"publisher","key":"e_1_2_9_5_1","DOI":"10.1242\/jcs.074773"},{"doi-asserted-by":"publisher","key":"e_1_2_9_6_1","DOI":"10.1038\/ng1511"},{"doi-asserted-by":"publisher","key":"e_1_2_9_7_1","DOI":"10.1056\/NEJMoa055695"},{"doi-asserted-by":"publisher","key":"e_1_2_9_8_1","DOI":"10.1111\/cge.13700"},{"doi-asserted-by":"publisher","key":"e_1_2_9_9_1","DOI":"10.1002\/ajmg.a.61508"}],"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.63075","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.63075","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63075","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T01:35:01Z","timestamp":1692322501000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,30]]},"references-count":8,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,3]]}},"alternative-id":["10.1002\/ajmg.a.63075"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63075","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2022,12,30]]},"assertion":[{"value":"2022-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}