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Dysregulation of the TGF\u2010\u00df pathway has been implicated in the pathogenesis of inherited disorders predisposing to thoracic aortic aneurysms syndromes (TAAS) including Marfan syndrome (MFS; <jats:italic>FBN1<\/jats:italic>) and Loeys\u2013Dietz syndrome (LDS; <jats:italic>TGFBR1<\/jats:italic>, <jats:italic>TGFBR2<\/jats:italic>, <jats:italic>TGFB2<\/jats:italic>, <jats:italic>TGFB3<\/jats:italic>, <jats:italic>SMAD2<\/jats:italic>, <jats:italic>SMAD3<\/jats:italic>). While these syndromes have distinct clinical criteria, they share clinical features including aortic root dilation and musculoskeletal findings. LTBP1 is a component of the TGF\u2010\u00df pathway that binds to fibrillin\u20101 in the extracellular matrix rendering TGF\u2010\u00df inactive. We describe a three\u2010generation family case series with a heterozygous \u223c5.1\u2009Mb novel contiguous gene deletion of chromosome 2p22.3\u2010p22.2 involving 11 genes, including <jats:italic>LTBP1<\/jats:italic>. The deletion has been identified in the proband, father and grandfather, who all have a phenotype consistent with a TAAS. Findings include thoracic aortic dilation, ptosis, malar hypoplasia, high arched palate, retrognathia, pes planus, hindfoot deformity, obstructive sleep apnea, and low truncal tone during childhood with joint laxity that progressed to reduced joint mobility over time. While the three affected individuals did not meet criteria for either MFS or LDS, they shared features of both. Although the deletion includes 11 genes, given the relationship between LTBP1, TGF\u2010\u00df, and fibrillin\u20101, <jats:italic>LTBP1<\/jats:italic> stands out as one of the possible candidate genes for the clinical syndrome observed in this family. More studies are necessary to evaluate the potential role of <jats:italic>LTBP1<\/jats:italic> in the pathophysiology of TAAS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.38590","type":"journal-article","created":{"date-parts":[[2018,1,19]],"date-time":"2018-01-19T11:13:21Z","timestamp":1516360401000},"page":"560-569","source":"Crossref","is-referenced-by-count":15,"title":["Three\u2010generation family with novel contiguous gene deletion on chromosome 2p22 associated with thoracic aortic aneurysm syndrome"],"prefix":"10.1002","volume":"176","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0917-478X","authenticated-orcid":false,"given":"Bianca","family":"Qui\u00f1ones\u2010P\u00e9rez","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"},{"name":"Division of General Pediatrics Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace E.","family":"VanNoy","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan C.","family":"Towne","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Cardiology Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj B.","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital Boston Massachusetts"},{"name":"Division of Newborn Medicine Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon E.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,1,19]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.017"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.887042"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513280200"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu744"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.01.040"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421807"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.7.3414"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2348"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2010.00437.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M909782199"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304412"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.131.2.539"},{"key":"e_1_2_7_14_1","first-page":"337","article-title":"Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene","volume":"352","author":"Dietz H. 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