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The objective of our study was to elucidate the wide variable phenotypic expressivity and incomplete penetrance in a three\u2010generation family with a truncating variant in <jats:italic>TBX4<\/jats:italic>. In addition to exome and genome sequencing analyses, a candidate noncoding regulatory single nucleotide variant (SNV) within the lung\u2010specific <jats:italic>TBX4<\/jats:italic> enhancer was functionally tested using an in vitro luciferase reporter assay. A heterozygous frameshift variant c.1112dup (p.Pro372Serfs*14) in <jats:italic>TBX4<\/jats:italic> was identified in patients with mild interstitial lung disease (1), bronchiolitis obliterans (1), recurrent pneumothorax (1), ICPPS\/SPS (1), LLDD (2), and in unaffected individuals (4). In two deceased neonates with LLDD, we identified a noncoding SNV rs62069651\u2010C located in <jats:italic>trans<\/jats:italic> to the mutated <jats:italic>TBX4<\/jats:italic> allele that reduced the <jats:italic>TBX4<\/jats:italic> promoter activity by 63% in the reporter assay. Our findings provide a functional evidence for the recently reported model of complex compound inheritance in which both <jats:italic>TBX4<\/jats:italic> coding and in <jats:italic>trans<\/jats:italic> noncoding hypomorphic variants in the lung\u2010specific enhancer of <jats:italic>TBX4<\/jats:italic> contribute to LLDD.<\/jats:p>","DOI":"10.1002\/ajmg.a.62656","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T09:51:37Z","timestamp":1643104297000},"page":"1420-1425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Exacerbation of mild lung disorders to lethal pulmonary hypoplasia by a noncoding hypomorphic <scp>SNV<\/scp> in a lung\u2010specific enhancer in <i>trans<\/i> to the frameshifting <scp><i>TBX4<\/i><\/scp> variant"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3251-8133","authenticated-orcid":false,"given":"Esra","family":"Y\u0131ld\u0131z B\u00f6l\u00fckba\u015f\u0131","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2340-4513","authenticated-orcid":false,"given":"Justyna A.","family":"Karolak","sequence":"additional","affiliation":[{"name":"Chair and Department of Genetics and Pharmaceutical Microbiology Poznan University of Medical Sciences  Poznan Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3886-2971","authenticated-orcid":false,"given":"Przemyslaw","family":"Szafranski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas 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Zedek Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2796-8399","authenticated-orcid":false,"given":"Gheona","family":"Altarescu","sequence":"additional","affiliation":[{"name":"Preimplantation Genetic Unit, Medical Genetics Institute Shaare Zedek Medical Center  Jerusalem Israel"}],"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 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