TY - JOUR
T1 - Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
AU - International 22q11.2 Brain and Behavior Consortium
AU - Zhao, Yingjie
AU - Diacou, Alexander
AU - Johnston, H. Richard
AU - Musfee, Fadi I.
AU - McDonald-McGinn, Donna M.
AU - McGinn, Daniel
AU - Crowley, T. Blaine
AU - Repetto, Gabriela M.
AU - Swillen, Ann
AU - Breckpot, Jeroen
AU - Vermeesch, Joris R.
AU - Kates, Wendy R.
AU - Digilio, M. Cristina
AU - Unolt, Marta
AU - Marino, Bruno
AU - Pontillo, Maria
AU - Armando, Marco
AU - Di Fabio, Fabio
AU - Vicari, Stefano
AU - van den Bree, Marianne
AU - Moss, Hayley
AU - Owen, Michael J.
AU - Murphy, Kieran C.
AU - Murphy, Clodagh M.
AU - Murphy, Declan
AU - Schoch, Kelly
AU - Shashi, Vandana
AU - Tassone, Flora
AU - Simon, Tony J.
AU - Shprintzen, Robert J.
AU - Campbell, Linda
AU - Philip, Nicole
AU - Heine-Suñer, Damian
AU - García-Miñaúr, Sixto
AU - Fernández, Luis
AU - Antonarakis, Stylianos E.
AU - Biondi, Massimo
AU - Boot, Erik
AU - Breetvelt, Elemi
AU - Busa, Tiffany
AU - Butcher, Nancy
AU - Buzzanca, Antonino
AU - Carmel, Miri
AU - Cleynen, Isabelle
AU - Cutler, David
AU - Dallapiccola, Bruno
AU - Guo, Tingwei
AU - Zhang, Zhengdong
AU - Wang, Tao
AU - Morrow, Bernice E.
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2020/1/2
Y1 - 2020/1/2
N2 - 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.
AB - 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.
KW - CRKL
KW - DiGeorge syndrome
KW - TBX1
KW - chromosome 22q11.2 deletion syndrome
KW - complex trait
KW - congenital heart disease
KW - conotruncal heart defects
KW - copy number variation
KW - genetic association
KW - genetic modifier
KW - haploinsufficiency
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U2 - 10.1016/j.ajhg.2019.11.010
DO - 10.1016/j.ajhg.2019.11.010
M3 - Article
AN - SCOPUS:85077046877
SN - 0002-9297
VL - 106
SP - 26
EP - 40
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -