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

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: Yingjie Zhao, Alexander Diacou, H Richard Johnston, Fadi I Musfee, Donna M McDonald-McGinn, Daniel McGinn, T Blaine Crowley, Gabriela M Repetto, Ann Swillen, Jeroen Breckpot, Joris R Vermeesch, Wendy R Kates, M Cristina Digilio, Marta Unolt, Bruno Marino, Maria Pontillo, Marco Armando, Fabio Di Fabio, Stefano Vicari, Marianne van den Bree, Hayley Moss, Michael J Owen, Kieran C Murphy, Clodagh M Murphy, Declan Murphy, Kelly Schoch, Vandana Shashi, Flora Tassone, Tony J Simon, Robert J Shprintzen, Linda Campbell, Nicole Philip, Damian Heine-Suñer, Sixto García-Miñaúr, Luis Fernández, International 22q11.2 Brain and Behavior Consortium, Carrie E Bearden, Claudia Vingerhoets, Therese van Amelsvoort, Stephan Eliez, Maude Schneider, Jacob A S Vorstman, Doron Gothelf, Elaine Zackai, A J Agopian, Raquel E Gur, Anne S Bassett, Beverly S Emanuel, Elizabeth Goldmuntz, Laura E Mitchell, Tao Wang, Bernice E Morrow
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 106 Issue 1 Pg. 26-40 (01 02 2020) ISSN: 1537-6605 [Electronic] United States
• PMID: 31870554 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• MAS1 protein, human
• Proto-Oncogene Mas

Topics

• Case-Control Studies
• Chromosome Deletion
• Chromosomes, Human, Pair 22 (genetics)
• Cohort Studies
• Female
• Genome-Wide Association Study
• Heart Defects, Congenital (genetics, pathology)
• Humans
• Linkage Disequilibrium
• Male
• Phenotype
• Polymorphism, Single Nucleotide
• Proto-Oncogene Mas
• Segmental Duplications, Genomic