{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:47:26Z","timestamp":1785743246831,"version":"3.56.0"},"reference-count":20,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":214,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HL165301-01A1"],"award-info":[{"award-number":["1R01HL165301-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Variants involving\n                    <jats:italic>TBX4<\/jats:italic>\n                    are associated with ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS; also known as small patella syndrome), pulmonary arterial hypertension (PAH), and lethal lung developmental disorders. The variability of penetrance and expressivity of\n                    <jats:italic>TBX4<\/jats:italic>\n                    variants remains a prominent challenge in understanding their genotype\u2013phenotype correlations. We investigated a five\u2010generation family with 12 affected individuals presenting with isolated ICPPS, lung\u2010related manifestations with features of ICPPS, and other milder abnormalities. Whole\u2010genome sequencing was used to identify the causative and putative modifying variants. Wefound a complex genomic rearrangement (CGR) involving the\n                    <jats:italic>TBX4<\/jats:italic>\n                    promoter and its 5\u2009\n                    <jats:sup>\u2032<\/jats:sup>\n                    untranslated region that segregated in the family. This CGR consists of an ~38\u2009bp insertion, an ~24\u2009bp deletion, an ~2.4\u2009kb deletion, and an ~235\u2009bp inversion. Computational analyses in the proband\u2032s mother with pulmonary and skeletal manifestations revealed 27 candidate modifying noncoding SNVs in the\n                    <jats:italic>TBX4<\/jats:italic>\n                    lung\u2010specific super\u2010enhancer and 45 SNVs within its topologically associating domain (TAD), including seven variants within the\n                    <jats:italic>TBX4<\/jats:italic>\n                    promoter. To explain the variable expressivity of this CGR, we propose that one or more of the variants within the\n                    <jats:italic>TBX4<\/jats:italic>\n                    lung\u2010specific super\u2010enhancer or TAD may act in\n                    <jats:italic>trans<\/jats:italic>\n                    with the pathogenic CGR, modulating\n                    <jats:italic>TBX4<\/jats:italic>\n                    expression from the intact allele.\n                  <\/jats:p>","DOI":"10.1155\/humu\/7278477","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:13:23Z","timestamp":1785741203000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Complex Genomic Rearrangement Involving the\n                    <i>TBX4<\/i>\n                    Promoter Manifesting With Variable Expressivity in a Five\u2010Generation Family"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5700-7789","authenticated-orcid":false,"given":"Shruti A.","family":"Pande","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2053-2477","authenticated-orcid":false,"given":"Hiuling","family":"Chan Joiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemyslaw","family":"Szafranski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Gambin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank P.","family":"Edenborough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael E.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-2340","authenticated-orcid":false,"given":"Shahin","family":"Moledina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2340-4513","authenticated-orcid":false,"given":"Justyna A.","family":"Karolak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-7490","authenticated-orcid":false,"given":"Pawel","family":"Stankiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202206-1039TR"},{"key":"e_1_2_10_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002866"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/421331"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101152"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01965-2018"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.12.010"},{"key":"e_1_2_10_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.10.013"},{"key":"e_1_2_10_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0232216"},{"key":"e_1_2_10_9_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202203-0485OC"},{"key":"e_1_2_10_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62656"},{"key":"e_1_2_10_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-020-0701-6"},{"key":"e_1_2_10_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00193.2017"},{"key":"e_1_2_10_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6222"},{"key":"e_1_2_10_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.08.010"},{"key":"e_1_2_10_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.70010"},{"key":"e_1_2_10_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddae169"},{"key":"e_1_2_10_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35418"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-08-0486"},{"key":"e_1_2_10_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.037"},{"key":"e_1_2_10_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.399"}],"container-title":["Human 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