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Although ACDMPV mostly results from single nucleotide variants (SNVs) or copy\u2010number variants (CNVs) involving <jats:italic>FOXF1<\/jats:italic>, AcDys, CAD, and PH are often associated with abnormalities within <jats:italic>TBX4<\/jats:italic> or <jats:italic>FGF10<\/jats:italic>. These genes interact in the SHH\u2010FOXF1 and TBX4\u2010FGF10 signaling network and are known regulators of lung development. Recent studies conducted in <jats:italic>TBX4\u2010<\/jats:italic>, <jats:italic>FGF10\u2010<\/jats:italic>, or <jats:italic>FOXF1\u2010<\/jats:italic>deficient LLDD lungs revealed decreased expression of <jats:italic>TMEM100<\/jats:italic> at the transcriptomic and immunohistochemical levels. Here, we present four new patients with genetically and histopathologically confirmed LLDD, including ACDMPV (<jats:italic>n<\/jats:italic>\u2009=\u20092), AcDys (<jats:italic>n<\/jats:italic>\u2009=\u20091), and PH (<jats:italic>n<\/jats:italic>\u2009=\u20091), in whom we detected a heterozygous variants involving <jats:italic>FOXF1<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20092) or <jats:italic>TBX4<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20092). Additional immunohistochemical (TMEM100) and qPCR analyses (<jats:italic>TMEM100<\/jats:italic>, <jats:italic>TBX4<\/jats:italic>, <jats:italic>FOXF1<\/jats:italic>) performed in lung tissues of these newborns revealed a significant reduction in <jats:italic>TMEM100<\/jats:italic>, <jats:italic>TBX4<\/jats:italic>, and <jats:italic>FOXF1<\/jats:italic> expression. Our results confirm previous findings indicating the possible involvement of <jats:italic>TMEM100<\/jats:italic> in FOXF1\u2010TBX4\u2010FGF10 molecular signaling that, when disrupted, may lead to LLDD.<\/jats:p>","DOI":"10.1002\/ajmg.a.64071","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T04:14:11Z","timestamp":1743308051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Decreased Level of <scp><i>TMEM100<\/i><\/scp> in Neonates With Lethal Lung Developmental Disorders due to Abnormalities in <scp>SHH<\/scp>\u2010<scp>FOXF1<\/scp> and <scp>TBX4<\/scp>\u2010<scp>FGF10<\/scp> Signaling Pathways"],"prefix":"10.1002","volume":"197","author":[{"given":"Katarzyna","family":"Bzd\u0119ga","sequence":"first","affiliation":[{"name":"Chair and Department of Genetics and Pharmaceutical Microbiology Poznan University of Medical Sciences  Poznan Poland"},{"name":"Doctoral School Poznan University of Medical Sciences  Poznan Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail H.","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":"Ma\u0142gorzata","family":"Rydzanicz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Medical University of Warsaw  Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witold","family":"B\u0142a\u017c","sequence":"additional","affiliation":[{"name":"Neonatal and Intensive Care Department Rzesz\u00f3w Provincial Hospital No. 2  Rzesz\u00f3w Poland"},{"name":"Faculty of Medicine, University of Rzesz\u00f3w  Rzesz\u00f3w Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Rafi\u0144ska\u2010Wa\u017cny","sequence":"additional","affiliation":[{"name":"Department of Neonatology Centrum Medyczne \u2018Ujastek\u2019  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna P.","family":"Terpin","sequence":"additional","affiliation":[{"name":"Pro\u2010Familia Hospital  Rzesz\u00f3w Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8821-9870","authenticated-orcid":false,"given":"Dariia","family":"Klepach","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care Unit Ukrainian Children's Cardiac Center  Kyiv Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentyna","family":"Zakharova","sequence":"additional","affiliation":[{"name":"Department of Pathology National M. 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