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Award)","award":["P50MH115716"],"award-info":[{"award-number":["P50MH115716"]}]},{"name":"Johns Hopkins University (Catalyst Award)","award":["R01GM11755"],"award-info":[{"award-number":["R01GM11755"]}]},{"name":"Johns Hopkins University (Catalyst Award)","award":["R03NS106486"],"award-info":[{"award-number":["R03NS106486"]}]},{"name":"Johns Hopkins University (Catalyst Award)","award":["R01HD114180"],"award-info":[{"award-number":["R01HD114180"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient with hypoplastic left heart syndrome and gross motor delay presented with a de novo mutation in SMC5. Modeling mutation of smc5 in Xenopus tropicalis embryos resulted in reduced heart size, decreased brain length, and disrupted pax6 patterning. To evaluate the cardiac development, we induced the conditional knockout (cKO) of Smc5 in mouse cardiomyocytes, which led to the depletion of mature cardiomyocytes and abnormal contractility. To test a role for Smc5 specifically in the brain, we induced cKO in the mouse central nervous system, which resulted in decreased brain volume, and diminished connectivity between areas related to motor function but did not affect vascular or brain ventricular volume. We propose that genetic factors, rather than hypoxia alone, can contribute when NDD and CHD cases occur concurrently.<\/jats:p>","DOI":"10.3390\/ijms25010430","type":"journal-article","created":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T09:35:21Z","timestamp":1703756121000},"page":"430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5190-1868","authenticated-orcid":false,"given":"Matthew P.","family":"O\u2019Brien","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina V.","family":"Pryzhkova","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA"},{"name":"Department of Biochemistry and Molecular Biology, Uniformed Services, University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8255-8013","authenticated-orcid":false,"given":"Evelyn M. R.","family":"Lake","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mandino","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchika","family":"Karnik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"Atkins","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle J.","family":"Xu","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhen","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Konstantino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Brueckner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura R.","family":"Ment","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa K.","family":"Khokha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"},{"name":"Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4890-2647","authenticated-orcid":false,"given":"Philip W.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA"},{"name":"Department of Biochemistry and Molecular Biology, Uniformed Services, University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1016\/j.jacc.2011.08.025","article-title":"Birth prevalence of congenital heart disease worldwide: A systematic review and meta-analysis","volume":"58","author":"Konings","year":"2011","journal-title":"J. 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