{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:06Z","timestamp":1760060646808,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Current Research funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The etiology of congenital diaphragmatic hernia (CDH) remains unknown in over 50% of cases, although multiple heterogeneous causative defects have been identified. Emerging evidence suggests that specific genes and molecular pathways involved in connective tissue biology may contribute to CDH development. Associations between CDH and connective tissue disorders have been reported, including cases in Marfan syndrome and a prevalence of CDH in 34% of patients with arterial tortuosity syndrome. Noticing joint laxity in several CDH patients, we aimed to investigate the presence of genetic variants linked to connective tissue disorders in this subgroup, focusing on patients enrolled in the follow-up program at Bambino Ges\u00f9 Children\u2019s Hospital. Methods: We selected patients diagnosed with CDH who also exhibited joint laxity based on a positive Beighton scale. These individuals underwent molecular analysis targeting genes known to be associated with heritable connective tissue disorders. Results: Genetic testing revealed variants in several genes across our patient series. These included mutations in FBN1, FBN2, ZNF469, VEGFA, NOTCH1, ELN, MCTP2, and SMAD6. In some cases, the variants were inherited paternally, while others appeared de novo. Most of these variants were classified as of unknown significance according to ACMG guidelines. Conclusions: (1) Several \u201cvariants of unknown significance\u201d in different genes causative for connective tissue disorders have been detected in half of the present series of patients with CDH and joint laxity; (2) although the majority of the variants are classified accordingly to the ACMG as \u201cvariants of unknown significance\u201d, a role of predisposition or susceptibility to CDH cannot be excluded; (3) a precise clinical evaluation for features of connective disorders should be recommended in the diagnostic workflow of patients with CDH.<\/jats:p>","DOI":"10.3390\/genes16091066","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"1066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Congenital Diaphragmatic Hernia and Joint Laxity: A Putative Link with Heritable Connective Tissue Disorders"],"prefix":"10.3390","volume":"16","author":[{"given":"Alessandra","family":"Di Pede","sequence":"first","affiliation":[{"name":"Medical and Neonatal Sub-Intensive Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monia","family":"Magliozzi","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Valfr\u00e9","sequence":"additional","affiliation":[{"name":"Neonatal and Pediatric Surgery Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9505-5906","authenticated-orcid":false,"given":"Maria Lisa","family":"Dentici","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flaminia","family":"Pugnaloni","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7514-5683","authenticated-orcid":false,"given":"Viola","family":"Alesi","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0191-1880","authenticated-orcid":false,"given":"Andrea","family":"Conforti","sequence":"additional","affiliation":[{"name":"Neonatal and Pediatric Surgery Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3090-2887","authenticated-orcid":false,"given":"Irma","family":"Capolupo","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annabella","family":"Braguglia","sequence":"additional","affiliation":[{"name":"Medical and Neonatal Sub-Intensive Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1260-6427","authenticated-orcid":false,"given":"Andrea","family":"Dotta","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Bagolan","sequence":"additional","affiliation":[{"name":"Neonatal and Pediatric Surgery Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-4297","authenticated-orcid":false,"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Digilio","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Ges\u00f9 Children\u2019s Hospital IRCCS, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1542\/pir.20.10.e71","article-title":"Congenital diaphragmatic hernia: The surgeon\u2019s perspective","volume":"10","author":"Skarsgard","year":"1999","journal-title":"Pediatr. 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