Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.
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.
Zhao, Y; Diacou, A; Johnston, HR; Musfee, FI; McDonald-McGinn, DM; McGinn, D; Crowley, TB; Repetto, GM; Swillen, A; Breckpot, J; Vermeesch, JR; Kates, WR; Digilio, MC; Unolt, M; Marino, B; Pontillo, M; Armando, M; Di Fabio, F; Vicari, S; van den Bree, M; Moss, H; Owen, MJ; Murphy, KC; Murphy, CM; Murphy, D; Schoch, K; Shashi, V; Tassone, F; Simon, TJ; Shprintzen, RJ; Campbell, L; Philip, N; Heine-Suñer, D; García-Miñaúr, S; Fernández, L; International 22q11.2 Brain and Behavior Consortium, ; Bearden, CE; Vingerhoets, C; van Amelsvoort, T; Eliez, S; Schneider, M; Vorstman, JAS; Gothelf, D; Zackai, E; Agopian, AJ; Gur, RE; Bassett, AS; Emanuel, BS; Goldmuntz, E; Mitchell, LE; Wang, T; Morrow, BE
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