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.

Keywords

Chromosome 22q11.2 deletion syndrome
DiGeorge syndrome
Congenital heart disease
Genetic modifier
Conotruncal heart defects
Copy number variation
Genetic association
CRKL
Haploinsufficiency
TBX1
Complex trait

UNIGE affiliation entities

Faculté de médecine / Section de médecine clinique / Département de psychiatrie

UNIGE research groups

Laboratoire d'imagerie et de psychopathologie développementale (693)

Citation (ISO format)

ZHAO, Yingjie et al. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects. In: American Journal of Human Genetics, 2020, vol. 106, n° 1, p. 26–40. doi: 10.1016/j.ajhg.2019.11.010

Article (Published version)

Identifiers

PID : unige:137334
DOI : 10.1016/j.ajhg.2019.11.010
PMID : 31870554

Additional URL for this publication

https://www.sciencedirect.com/science/article/pii/S0002929719304318

Journal ISSN

0002-9297

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01/04/2020 15:01:00

First validation

01/04/2020 15:01:00

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13/10/2025 17:18:29

Status update

15/03/2023 22:08:56

Last indexation

10/11/2026 17:37:38

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

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