Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects Academic Article uri icon

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.

authors

  • Zhao, Yingjie
  • 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, Flora
  • Simon, TJ
  • Shprintzen, RJ
  • Campbell, L
  • Philip, N
  • Heine-Suñer, D
  • García-Miñaúr, S
  • Fernández, L
  • Antonarakis, SE
  • Biondi, M
  • Boot, E
  • Breetvelt, E
  • Busa, T
  • Butcher, N
  • Buzzanca, A
  • Carmel, M
  • Cleynen, I
  • Cutler, D
  • Dallapiccola, B
  • de la Fuente Sanches, MA
  • Epstein, MP
  • Evers, R
  • Fernandez, L
  • Fritsch, R
  • Algas, FG
  • Guo, T
  • Gur, R
  • Hestand, MS
  • Heung, T
  • Hooper, S
  • Jin, A
  • Kushan-Wells, L
  • Laorden-Nieto, AT
  • Lattanzi, G
  • Marshall, C
  • McCabe, K
  • Michaelovsky, E
  • Ornstein, C
  • Silversides, C
  • Tran, O
  • van Duin, EDA
  • Vergaelen, E
  • Warren, ST
  • Weinberger, R
  • Weizman, A
  • Zhang, Z
  • Zwick, M
  • 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

publication date

  • 2020