{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:22:43Z","timestamp":1785777763415,"version":"3.56.0"},"reference-count":18,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"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\u201001A1"],"award-info":[{"award-number":["1R01HL165301\u201001A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004421","name":"Politechnika Warszawska","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004421","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2020\/37\/B\/NZ2\/03757"],"award-info":[{"award-number":["2020\/37\/B\/NZ2\/03757"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Single nucleotide variants (SNVs) and copy\u2010number variant (CNV) deletions involving\n                    <jats:italic>TBX4<\/jats:italic>\n                    have been associated with pulmonary arterial hypertension, ischiocoxopodopatellar syndrome, and lethal lung developmental disorders (LLDDs). Thus far, all large CNV deletions encompassing entire\n                    <jats:italic>TBX4<\/jats:italic>\n                    have been found to have arisen de novo. Here, we present a three\u2010generation family with three neonate siblings who died within 35\u201366\u2009days due to histopathologically diagnosed LLDD. Whole\u2010genome sequencing identified an ~108\u2010kb CNV deletion encompassing\n                    <jats:italic>TBX4<\/jats:italic>\n                    in all three infants. The deletion was also found in their mother with a history of pneumonia and persistent thick upper airway secretions and in the maternal grandfather who had surgically corrected genu valgum. RT\u2010qPCR from the proband's lung biopsy showed a decrease of\n                    <jats:italic>TBX4<\/jats:italic>\n                    transcript level greater than 50%, suggesting additional deregulation of\n                    <jats:italic>TBX4<\/jats:italic>\n                    expression. Computational analyses of the\n                    <jats:italic>TBX4<\/jats:italic>\n                    super\u2010enhancer identified 15 candidate noncoding hypomorphic SNVs transmitted to the children exclusively from their father and absent in their mother and maternal grandfather. We show that SNV rs35827636T\u2009&gt;\u2009C, previously proposed as potentially hypomorphic in an unrelated AcDys patient, reduced transcriptional activity of the\n                    <jats:italic>TBX4<\/jats:italic>\n                    promoter in an episomal reporter assay. Moreover, Hi\u2010C analysis predicted inter\u2010TAD interaction between the\n                    <jats:italic>TBX4<\/jats:italic>\n                    super\u2010enhancer and its promoter\u2010proximal region. Our data further demonstrate complex compound inheritance of LLDDs and resulting challenges for genetic counseling.\n                  <\/jats:p>","DOI":"10.1111\/cge.70010","type":"journal-article","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T06:25:43Z","timestamp":1750487143000},"page":"161-166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Highly Variable Expressivity of a\n                    <scp>CNV<\/scp>\n                    Deletion Involving\n                    <scp>\n                      <i>TBX4<\/i>\n                    <\/scp>\n                    in Three Deceased Siblings With Lung Developmental Disorder and Their Mildly Affected Mother and Grandfather"],"prefix":"10.1111","volume":"109","author":[{"given":"Przemyslaw","family":"Szafranski","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Gambin","sequence":"additional","affiliation":[{"name":"Institute of Computer Science, Warsaw University of Technology  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kadlof","sequence":"additional","affiliation":[{"name":"Faculty of Mathematics and Information Science, Warsaw University of Technology  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Denkiewicz","sequence":"additional","affiliation":[{"name":"Faculty of Mathematics and Information Science, Warsaw University of Technology  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3840-7610","authenticated-orcid":false,"given":"Dariusz","family":"Plewczynski","sequence":"additional","affiliation":[{"name":"Faculty of Mathematics and Information Science, Warsaw University of Technology  Warsaw Poland"},{"name":"Centre of New Technologies, University of Warsaw  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Jeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahir","family":"Cortes\u2010Santiago","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Pathology, Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salmo","family":"Raskin","sequence":"additional","affiliation":[{"name":"Laboratorio Genetika, and Postgraduate Program in Child and Adolescent, Department of Pediatrics Federal University of Paran\u00e1  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-7490","authenticated-orcid":false,"given":"Pawe\u0142","family":"Stankiewicz","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101152"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00211-2016"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.117.001887"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01965-2018"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37822"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2018.10.018"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.12.010"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61096"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.01.038"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62656"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-020-0701-6"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14428"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe5407"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/jdb12030024"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.23773"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2020.12.015"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01223-8"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01681-2"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70010","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70010","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70010","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T09:02:51Z","timestamp":1779786171000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,21]]},"references-count":18,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1111\/cge.70010"],"URL":"https:\/\/doi.org\/10.1111\/cge.70010","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/CGE.70010\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70010\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70010\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70010\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70010\/v1\/decision1","asserted-by":"object"}]},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,21]]},"assertion":[{"value":"2025-04-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}