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Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS

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dc.contributor.authorRepetto, Gabriela
dc.contributor.authorZhao, Yingjie
dc.contributor.authorWang, Yujue
dc.contributor.authorShi, Lijie
dc.contributor.authorMcDonald, Donna
dc.contributor.authorCrowley, Blaine
dc.contributor.authorMcGinn, Daniel
dc.contributor.authorTran, Oanh
dc.contributor.authorMiller, Daniella
dc.contributor.authorLin, Jhih-Rong
dc.contributor.authorZacka, Elaine
dc.contributor.authorJohnston, Richard
dc.contributor.authorChow, Eva
dc.contributor.authorVorstman, Jacob
dc.contributor.authorVingerhoets, Claudia
dc.contributor.authorVan Amelsvoort, Therese
dc.contributor.authorGothelf, Doron
dc.contributor.authorSwillen, Ann
dc.contributor.authorBreckpot, Jeroen
dc.contributor.authorVermeesch, Joris
dc.contributor.authorEliez, Stephan
dc.contributor.authorSchneider, Maude
dc.contributor.authorVan den Bree, Marianne
dc.contributor.authorOwen, Michael
dc.contributor.authorKates, Wendy
dc.contributor.authorShashi, Vandana
dc.contributor.authorSchoch, Kelly
dc.contributor.authorBearden, Carrie
dc.contributor.authorDigili, M. Cristina
dc.contributor.authorUnolt, Marta
dc.contributor.authorPutotto, Carolina
dc.contributor.authorMarino, Bruno
dc.contributor.authorPontillo, Maria
dc.contributor.authorArmando, Marco
dc.contributor.authorVicar, Stefano
dc.contributor.authorAngkustsiri, Kathleen
dc.contributor.authorCampbell, Linda
dc.contributor.authorBusa, Tiffany
dc.contributor.authorHeine, Damian
dc.contributor.authorMurphy, Kieran
dc.contributor.authorMurphy, Declan
dc.date.accessioned2024-03-11T14:26:16Z
dc.date.available2024-03-11T14:26:16Z
dc.date.issued2023
dc.descriptionGarcía, Sixto; Fernández, Luis; Zhang, Zhengdong; Goldmuntz, Elizabeth; Gu, Raquel; Emanuel, Beverly; Zheng, Deyou; Marshal, Christian; Basset,Anne; Wang, Tao; Morrow, Bernice,
dc.description.abstractCongenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD
dc.description.versionVersión publicada
dc.identifier.doihttps://doi.org/10.1038/s41525-023-00363-y
dc.identifier.urihttps://hdl.handle.net/11447/8512
dc.language.isoen
dc.subject22q11.2DS
dc.subjectTBX1 network
dc.subjectChromatin regulators
dc.subjectCongenital heart disease
dc.subjectHaploinsufficiency of TBX1
dc.titleChromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceNPJ genomic medicine
dspace.entity.typePublication
relation.isAuthorOfPublication98c75303-d87e-4c17-9d27-d9d710229223
relation.isAuthorOfPublication.latestForDiscovery98c75303-d87e-4c17-9d27-d9d710229223

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