학술논문
Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
Document Type
article
Author
Zhao, Yingjie; Diacou, Alexander; Johnston, H Richard; Musfee, Fadi I; McDonald-McGinn, Donna M; McGinn, Daniel; Crowley, T Blaine; Repetto, Gabriela M; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris R; Kates, Wendy R; Digilio, M Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; van den Bree, Marianne; Moss, Hayley; Owen, Michael J; Murphy, Kieran C; Murphy, Clodagh M; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora; Simon, Tony J; Shprintzen, Robert J; Campbell, Linda; Philip, Nicole; Heine-Suñer, Damian; García-Miñaúr, Sixto; Fernández, Luis; Consortium, International 22q11 2 Brain and Behavior; Antonarakis, Stylianos E; Biondi, Massimo; Boot, Erik; Breetvelt, Elemi; Busa, Tiffany; Butcher, Nancy; Buzzanca, Antonino; Carmel, Miri; Cleynen, Isabelle; Cutler, David; Dallapiccola, Bruno; de la Fuente Sanches, María Angeles; Epstein, Michael P; Evers, Rens; Fernandez, Luis; Fritsch, Rosemarie; Algas, Fernando García; Guo, Tingwei; Gur, Raquel; Hestand, Matthew S; Heung, Tracy; Hooper, Stephen; Jin, Andrea; Kushan-Wells, Leila; Laorden-Nieto, Alejandra Teresa; Lattanzi, Guido; Marshall, Christian; McCabe, Kathryn; Michaelovsky, Elena; Ornstein, Claudia; Silversides, Candice; Tran, Oanh; van Duin, Esther DA; Vergaelen, Elfi; Warren, Steve T; Weinberger, Ronnie; Weizman, Abraham; Zhang, Zhengdong; Zwick, Michael; Bearden, Carrie E; Vingerhoets, Claudia; van Amelsvoort, Therese; Eliez, Stephan; Schneider, Maude; Vorstman, Jacob AS; Gothelf, Doron; Zackai, Elaine; Agopian, AJ; Gur, Raquel E; Bassett, Anne S; Emanuel, Beverly S; Goldmuntz, Elizabeth; Mitchell, Laura E; Wang, Tao; Morrow, Bernice E
Source
American Journal of Human Genetics. 106(1)
Subject
Language
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.