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

Research output: Contribution to journalArticle


  • International 22q11.2 Brain and Behavior Consortium

External Institution(s)

  • See Table S1
  • Yeshiva University
  • Emory University
  • School of Public Health
  • University of Pennsylvania
  • Universidad del Desarrollo
  • KU Leuven
  • SUNY Upstate Medical University
  • IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • University of Rome La Sapienza
  • University of Geneva
  • Catholic University of the Sacred Heart
  • Cardiff University
  • Royal College of Surgeons in Ireland
  • King's College London
  • South London and Maudsley NHS Foundation Trust
  • Duke University
  • University of California at Davis Medical Center
  • Virtual Center for Velo-Cardio-Facial Syndrome
  • University of Newcastle
  • Aix Marseille Universite
  • Hospital Son Dureta
  • Universidad Autónoma de Madrid
  • University of California at Los Angeles
  • Maastricht University
  • Research Institute
  • University of Toronto
  • Utrecht University
  • Sheba Medical Center at Tel Hashomer
  • Clinical Genetics Research Program
  • University Health Network


Original languageEnglish (US)
Pages (from-to)26-40
Number of pages15
JournalAmerican journal of human genetics
Issue number1
StatusPublished - Jan 2 2020


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.

    Research areas

  • CRKL, DiGeorge syndrome, TBX1, chromosome 22q11.2 deletion syndrome, complex trait, congenital heart disease, conotruncal heart defects, copy number variation, genetic association, genetic modifier, haploinsufficiency

Citation formats



International 22q11.2 Brain and Behavior Consortium 2020, 'Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects', American journal of human genetics, vol. 106, no. 1, pp. 26-40.