Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

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dc.contributor.authorZhao, Yingjie
dc.contributor.authorDiacou, Alexander
dc.contributor.authorJohnston, H. Richard
dc.contributor.authorMusfee, Fadi I
dc.contributor.authorMcDonald-McGinn, Donna M.
dc.contributor.authorMcGinn, Daniel
dc.contributor.authorCrowley, T. Blaine
dc.contributor.authorRepetto, Gabriela
dc.contributor.authorSwillen, Ann
dc.contributor.authorBreckpot, Jeroen
dc.contributor.authorVermeesch, Joris R
dc.contributor.authorKates, Wendy R.
dc.contributor.authorDigilio, M. Cristina
dc.contributor.authorUnolt, Marta
dc.contributor.authorMarino, Bruno
dc.contributor.authorPontillo, Maria
dc.contributor.authorArmando, Marco
dc.contributor.authorDi Fabio, Fabio
dc.contributor.authorVicari, Stefano
dc.contributor.authorBree, Marianne van den
dc.contributor.authorMoss, Hayley
dc.contributor.authorOwen, Michael J.
dc.contributor.authorMurphy, Kieran C.
dc.contributor.authorMurphy, Clodagh M.
dc.contributor.authorMurphy, Declan
dc.contributor.authorSchoch, Kelly
dc.contributor.authorShashi, Vandana
dc.contributor.authorTassone, Flora
dc.contributor.authorSimon, Tony J.
dc.contributor.authorShprintzen, Robert J.
dc.contributor.authorCampbell, Linda
dc.contributor.authorPhilip, Nicole
dc.contributor.authorHeine-Suñer, Damian
dc.contributor.authorGarcía-Miñaúr, Sixto
dc.contributor.authorFernández, Luis
dc.contributor.authorBearden, Carrie E.
dc.contributor.authorVingerhoets, Claudia
dc.contributor.authorAmelsvoort, Therese van
dc.contributor.authorEliez, Stephan
dc.contributor.authorSchneider, Maude
dc.contributor.authorVorstman, Jacob A. S.
dc.contributor.authorGothelf, Doron
dc.contributor.authorZackai, Elaine
dc.contributor.authorAgopian, A. J.
dc.contributor.authorGur, Raquel E.
dc.contributor.authorBassett, Anne S.
dc.contributor.authorEmanuel, Beverly S.
dc.contributor.authorGoldmuntz, Elizabeth
dc.contributor.authorMitchell, Laura E.
dc.contributor.authorWang, Tao
dc.contributor.authorMorrow, Bernice E.
dc.date.accessioned2021-07-06T15:58:04Z
dc.date.available2021-07-06T15:58:04Z
dc.date.issued2020
dc.description.abstractThe 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.es
dc.format.extent16 p.es
dc.identifier.citationAmerican Journal of Human Genetics . 2020 Jan 2;106(1):26-40es
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2019.11.010es
dc.identifier.urihttp://hdl.handle.net/11447/4133
dc.language.isoenes
dc.subjectCRKLes
dc.subjectDiGeorge syndromees
dc.subjectTBX1es
dc.subjectChromosome 22q11.2 deletion syndromees
dc.subjectComplex traites
dc.subjectCongenital heart diseasees
dc.subjectConotruncal heart defectses
dc.subjectCopy number variationes
dc.subjectGenetic associationes
dc.subjectGenetic modifier; haploinsufficiency.es
dc.subjectHaploinsufficiencyes
dc.titleComplete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defectses
dc.typeArticlees

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