dc.creator | Zhao, Yingjie | |
dc.creator | Diacou, Alexander | |
dc.creator | Johnston, Richard | |
dc.creator | Musfee, Fadi | |
dc.creator | McDonald-McGinn, Donna | |
dc.creator | McGinn, Daniel | |
dc.creator | Crowley, Blaine | |
dc.creator | Repetto, Gabriela | |
dc.creator | Swillen, Ann | |
dc.creator | Breckpot, Jeroen | |
dc.creator | Vermeesch, Joris | |
dc.creator | Kates, Wendy | |
dc.creator | Digilio, Cristina | |
dc.creator | Unolt, Marta | |
dc.creator | Marino, Bruno | |
dc.creator | Pontillo, Maria | |
dc.creator | Armando, Marco | |
dc.creator | Di Fabio, Fabio | |
dc.creator | Vicari, Stefano | |
dc.creator | van den Bree, Marianne | |
dc.creator | Moss, Hayley | |
dc.creator | Owen, Michael | |
dc.creator | Murphy, Kieran | |
dc.creator | Murphy, Clodagh | |
dc.creator | Murphy, Declan | |
dc.creator | Schoch, Kelly | |
dc.creator | Shashi, Vandana | |
dc.creator | Tassone, Flora | |
dc.date.accessioned | 2020-09-11T15:09:12Z | |
dc.date.accessioned | 2023-05-19T14:47:00Z | |
dc.date.available | 2020-09-11T15:09:12Z | |
dc.date.available | 2023-05-19T14:47:00Z | |
dc.date.created | 2020-09-11T15:09:12Z | |
dc.date.issued | 2020-01 | |
dc.identifier | Zhao Y, Diacou A, Johnston HR, et al. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects. Am J Hum Genet. 2020;106(1):26-40. doi:10.1016/j.ajhg.2019.11.010 | |
dc.identifier | https://doi.org/10.1016/j.ajhg.2019.11.010. | |
dc.identifier | http://hdl.handle.net/11447/3428 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/6301792 | |
dc.description.abstract | The 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. | |
dc.language | en | |
dc.publisher | American Society of Human Genetics by Elsevier Inc. | |
dc.subject | CRKL | |
dc.subject | DiGeorge syndrome | |
dc.subject | TBX1 | |
dc.subject | Cchromosome 22q11.2 deletion syndrome | |
dc.subject | Complex trait | |
dc.subject | Congenital heart disease | |
dc.subject | Conotruncal heart defects | |
dc.subject | Copy number variation | |
dc.subject | Genetic association | |
dc.subject | Genetic modifier | |
dc.subject | Haploinsufficiency | |
dc.title | Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects | |
dc.type | Article | |