- Title
- Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects
- Creator
- 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; Campbell, Linda; 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.; Philip, Nicole; Heine-Suñer, Damian; García-Miñaúr, Sixto; Fernández, Luis; 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, Maria Angeles; Epstein, Michael P.; Evers, Rens; Fernandez, L; Fritsch, Rosemarie; Algas, Fernando Garcia; Guo, Tingwei; Gur, Raquel; Hestand, Matthew S.; Heung, Tracy; Hooper, Stephen; Jin, Andrea; Kushan-Wells, Leila; Laorden-Nieto, Alejandra Terese; Lattanzi, Guido; Marshall, Christian; McCabe, Kathryn; Michaelovsky, Elena; Ornstein, Claudia; Silversides, Candice; Tran, Oanh; van Duin, Esther D. A.; 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 A. S.; Gothelf, Doron; Zackai, Elaine; Agopian, A. J.; Gur, Raquel E.; Bassett, Anne S.; Emanuel, Beverly S.; Goldmuntz, Elizabeth; Mitchell, Laura E.; Wang, Tao; Morrow, Bernice E.
- Relation
- American Journal of Human Genetics Vol. 106, Issue 1, p. 26-40
- Publisher Link
- http://dx.doi.org/10.1016/j.ajhg.2019.11.010
- Publisher
- Cell Press
- Resource Type
- journal article
- Date
- 2020
- Description
- 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.
- Subject
- chromosome 22q11.2 deletion syndrome; DiGeorge syndrome; congenital heart disease; genetic modifier; conotruncal heart defects; copy number variation; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1463736
- Identifier
- uon:46821
- Identifier
- ISSN:0002-9297
- Language
- eng
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