{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T04:08:17Z","timestamp":1767845297997,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Congenital diaphragmatic hernia (CDH) is a major birth anomaly that often occurs with additional non-hernia-related malformations, and is then referred to as CDH+. While the impact of genetic alterations does not play a major role in isolated CDH, patients with CDH+ display mutations that are usually determined via array-based comparative genomic hybridization (aCGH). We analyzed 43 patients with CDH+ between 2012 and 2021 to identify novel specific mutations via aCGH associated with CDH+ and its outcome. Deletions (n = 32) and duplications (n = 29) classified as either pathological or variants of unknown significance (VUS) could be detected. We determined a heterozygous deletion of approximately 3.75 Mb located at 8p23.1 involving several genes including GATA4, NEIL2, SOX7, and MSRA, which was consequently evaluated as pathological. Another heterozygous deletion within the region of 9p23 (9,972,017-10,034,230 kb) encompassing the Protein Tyrosine Phosphatase Receptor Type Delta gene (PTPRD) was identified in 2 patients. This work expands the knowledge of genetic alterations associated with CDH+ and proposes two novel candidate genes discovered via aCGH.<\/jats:p>","DOI":"10.3390\/jcm12196111","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T03:44:42Z","timestamp":1695354282000},"page":"6111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["aCGH Analysis Reveals Novel Mutations Associated with Congenital Diaphragmatic Hernia Plus (CDH+)"],"prefix":"10.3390","volume":"12","author":[{"given":"Yannick","family":"Schreiner","sequence":"first","affiliation":[{"name":"Department of Neonatology, University Children\u2019s Hospital Mannheim, University of Heidelberg, 69117 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Stoll","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University Children\u2019s Hospital Mannheim, University of Heidelberg, 69117 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, University Hospital Mannheim, University of Heidelberg, 68167 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meike","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, University of Heidelberg, 69117 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Hetjens","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, University of Heidelberg, 69117 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Steck","sequence":"additional","affiliation":[{"name":"SYNLAB Centre for Human Genetics, 68163 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2246-7982","authenticated-orcid":false,"given":"Alba","family":"Perez Ortiz","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University Children\u2019s Hospital Mannheim, University of Heidelberg, 69117 Mannheim, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neysan","family":"Rafat","sequence":"additional","affiliation":[{"name":"Department of Neonatology, University Children\u2019s Hospital Mannheim, University of Heidelberg, 69117 Mannheim, Germany"},{"name":"Department of Neonatology, Center for Children, Adolescent and Women\u2019s Medicine, Olgahospital, Klinikum Stuttgart, 70174 Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1053\/jpsu.2000.8725","article-title":"Congenital diaphragmatic hernia: A meta-analysis of mortality factors","volume":"35","author":"Skari","year":"2000","journal-title":"J. Pediatr. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1002\/bdr2.1106","article-title":"Epidemiology and prognosis of congenital diaphragmatic hernia: A population-based cohort study in Utah","volume":"109","author":"Shanmugam","year":"2017","journal-title":"Birth Defects Res."},{"key":"ref_3","unstructured":"Longoni, M., Pober, B.R., High, F.A., Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (2020). GeneReviews\u00ae[Internet], University of Washington."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cannata, G., Caporilli, C., Grassi, F., Perrone, S., and Esposito, S. (2021). Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126353"},{"key":"ref_5","unstructured":"Yu, L., Hernan, R.R., Wynn, J., and Chung, W.K. (2019). Seminars in Perinatology, Elsevier."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1038\/s41431-021-00972-0","article-title":"Genetics of diaphragmatic hernia","volume":"29","author":"Schreiner","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0925-4773(97)00167-6","article-title":"Identification of a mechanism to localize generation of retinoic acid in rat embryos","volume":"69","author":"Ward","year":"1997","journal-title":"Mech. Dev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1242\/dev.120.10.2749","article-title":"Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants","volume":"120","author":"Mendelsohn","year":"1994","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0002-9440(10)63861-8","article-title":"Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents","volume":"162","author":"Mey","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1165\/rcmb.2009-0076OC","article-title":"Understanding abnormal retinoid signaling as a causative mechanism in congenital diaphragmatic hernia","volume":"42","author":"Clugston","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"L665","DOI":"10.1152\/ajplung.00027.2008","article-title":"Gene expression in the developing diaphragm: Significance for congenital diaphragmatic hernia","volume":"294","author":"Clugston","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00439-012-1249-0","article-title":"Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia","volume":"132","author":"Yu","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1002\/ajmg.a.35965","article-title":"Prenatal diagnosis of two fetuses with deletions of 8p23. 1, critical region for congenital diaphragmatic hernia and heart defects","volume":"161","author":"Keitges","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ackerman, K.G., Herron, B.J., Vargas, S.O., Huang, H., Tevosian, S.G., Kochilas, L., Rao, C., Pober, B.R., Babiuk, R.P., and Epstein, J.A. (2005). Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet., 1.","DOI":"10.1371\/journal.pgen.0010010"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1038\/sj.ejhg.5201872","article-title":"Candidate genes for congenital diaphragmatic hernia from animal models: Sequencing of FOG2 and PDGFR\u03b1 reveals rare variants in diaphragmatic hernia patients","volume":"15","author":"Bleyl","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/uog.2651","article-title":"Assessment of lung area in normal fetuses at 12\u201332 weeks","volume":"26","author":"Peralta","year":"2005","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1164\/ajrccm.163.7.2011060","article-title":"Bronchopulmonary dysplasia","volume":"163","author":"Jobe","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"856","DOI":"10.2214\/AJR.15.15018","article-title":"Correlation of observed-to-expected MRI fetal lung volume and ultrasound lung-to-head ratio at different gestational times in fetuses with congenital diaphragmatic hernia","volume":"206","author":"Kastenholz","year":"2016","journal-title":"Am. J. Roentgenol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Khan, M.A., Rafiq, M.A., Noor, A., Ali, N., Ali, G., Vincent, J.B., and Ansar, M. (2011). A novel deletion mutation in the TUSC3 gene in a consanguineous Pakistani family with autosomal recessive nonsyndromic intellectual disability. BMC Med. Genet., 12.","DOI":"10.1186\/1471-2350-12-56"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/8904_2014_390","article-title":"Homozygous truncating intragenic duplication in TUSC3 responsible for rare autosomal recessive nonsyndromic intellectual disability with no clinical or biochemical metabolic markers","volume":"20","author":"Bonnet","year":"2014","journal-title":"JIMD Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1002\/ajmg.a.36028","article-title":"Homozygous deletion in TUSC3 causing syndromic intellectual disability: A new patient","volume":"161","author":"Loddo","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.ajhg.2008.03.018","article-title":"A defect in the TUSC3 gene is associated with autosomal recessive mental retardation","volume":"82","author":"Garshasbi","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13039-015-0149-0","article-title":"Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability","volume":"8","author":"Choucair","year":"2015","journal-title":"Mol. Cytogenet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1002\/ajmg.a.32896","article-title":"Chromosome 8p23. 1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia","volume":"149","author":"Wat","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4115","DOI":"10.1093\/hmg\/dds241","article-title":"Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23. 1","volume":"21","author":"Wat","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/ng.3250","article-title":"Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias","volume":"47","author":"Merrell","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1136\/jmedgenet-2012-101135","article-title":"De novo copy number variants are associated with congenital diaphragmatic hernia","volume":"49","author":"Yu","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0070-2153(07)80003-2","article-title":"Substrates of the methionine sulfoxide reductase system and their physiological relevance","volume":"80","author":"Oien","year":"2007","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.bbrc.2017.01.025","article-title":"Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen","volume":"484","author":"Singh","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.ajhg.2008.03.021","article-title":"Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation","volume":"82","author":"Molinari","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Fan, X., Zhang, X., Shen, J., Zhao, H., Yu, X., Chen, Y., Zhuang, Z., Deng, X., Feng, H., and Wang, Y. (2016). Decreased TUSC3 promotes pancreatic cancer proliferation, invasion and metastasis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149028"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.yexcr.2018.08.012","article-title":"TUSC3 accelerates cancer growth and induces epithelial-mesenchymal transition by upregulating claudin-1 in non-small-cell lung cancer cells","volume":"373","author":"Feng","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00016.2002","article-title":"Receptor protein tyrosine phosphatases in nervous system development","volume":"83","author":"Johnson","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5872","DOI":"10.1523\/JNEUROSCI.0386-06.2006","article-title":"Mammalian motoneuron axon targeting requires receptor protein tyrosine phosphatases \u03c3 and \u03b4","volume":"26","author":"Uetani","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1136\/jmedgenet-2020-107317","article-title":"Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH","volume":"59","author":"Scott","year":"2022","journal-title":"J. Med. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/19\/6111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:55:27Z","timestamp":1760129727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/19\/6111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,22]]},"references-count":35,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12196111"],"URL":"https:\/\/doi.org\/10.3390\/jcm12196111","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,22]]}}}