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

International 22q11.2 Brain and Behavior Consortium; Rosemarie Fritsch

doi:10.1016/j.ajhg.2019.11.010

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

International 22q11.2 Brain and Behavior Consortium, Rosemarie Fritsch

Facultad de Medicina

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

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.

Original language	English
Pages (from-to)	26-40
Number of pages	15
Journal	American Journal of Human Genetics
Volume	106
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2019.11.010
State	Published - 2 Jan 2020

Bibliographical note

Funding Information:
We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577, R01HL084410, U01MH101720, U54HD090260, and P01HD070454. Other funding sources are detailed in the Supplemental Information.

Funding Information:
We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577 , R01HL084410 , U01MH101720 , U54HD090260 , and P01HD070454 . Other funding sources are detailed in the Supplemental Information .

Publisher Copyright:
© 2019 American Society of Human Genetics

Keywords

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

Access to Document

10.1016/j.ajhg.2019.11.010

Cite this

@article{ed59c1add6e5490bbdc45d2cdf944eca,

title = "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.",

keywords = "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",

author = "{International 22q11.2 Brain and Behavior Consortium} and Yingjie Zhao and Alexander Diacou and Johnston, {H. Richard} and Musfee, {Fadi I.} and McDonald-McGinn, {Donna M.} and Daniel McGinn and Crowley, {T. Blaine} and Repetto, {Gabriela M.} and Ann Swillen and Jeroen Breckpot and Vermeesch, {Joris R.} and Kates, {Wendy R.} and Digilio, {M. Cristina} and Marta Unolt and Bruno Marino and Maria Pontillo and Marco Armando and {Di Fabio}, Fabio and Stefano Vicari and {van den Bree}, Marianne and Hayley Moss and Owen, {Michael J.} and Murphy, {Kieran C.} and Murphy, {Clodagh M.} and Declan Murphy and Kelly Schoch and Vandana Shashi and Flora Tassone and Simon, {Tony J.} and Shprintzen, {Robert J.} and Linda Campbell and Nicole Philip and Damian Heine-Su{\~n}er and Sixto Garc{\'i}a-Mi{\~n}a{\'u}r and Luis Fern{\'a}ndez and Antonarakis, {Stylianos E.} and Massimo Biondi and Erik Boot and Elemi Breetvelt and Tiffany Busa and Nancy Butcher and Antonino Buzzanca and Miri Carmel and Isabelle Cleynen and David Cutler and Bruno Dallapiccola and {de la Fuente Sanches}, {Mar{\'i}a Angeles} and Epstein, {Michael P.} and Rens Evers and Luis Fernandez and Rosemarie Fritsch",

note = "Funding Information: We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577, R01HL084410, U01MH101720, U54HD090260, and P01HD070454. Other funding sources are detailed in the Supplemental Information. Funding Information: We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577 , R01HL084410 , U01MH101720 , U54HD090260 , and P01HD070454 . Other funding sources are detailed in the Supplemental Information . Publisher Copyright: {\textcopyright} 2019 American Society of Human Genetics",

year = "2020",

month = jan,

day = "2",

doi = "10.1016/j.ajhg.2019.11.010",

language = "English",

volume = "106",

pages = "26--40",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

AU - International 22q11.2 Brain and Behavior Consortium

AU - Zhao, Yingjie

AU - Diacou, Alexander

AU - Johnston, H. Richard

AU - Musfee, Fadi I.

AU - McDonald-McGinn, Donna M.

AU - McGinn, Daniel

AU - Crowley, T. Blaine

AU - Repetto, Gabriela M.

AU - Swillen, Ann

AU - Breckpot, Jeroen

AU - Vermeesch, Joris R.

AU - Kates, Wendy R.

AU - Digilio, M. Cristina

AU - Unolt, Marta

AU - Marino, Bruno

AU - Pontillo, Maria

AU - Armando, Marco

AU - Di Fabio, Fabio

AU - Vicari, Stefano

AU - van den Bree, Marianne

AU - Moss, Hayley

AU - Owen, Michael J.

AU - Murphy, Kieran C.

AU - Murphy, Clodagh M.

AU - Murphy, Declan

AU - Schoch, Kelly

AU - Shashi, Vandana

AU - Tassone, Flora

AU - Simon, Tony J.

AU - Shprintzen, Robert J.

AU - Campbell, Linda

AU - Philip, Nicole

AU - Heine-Suñer, Damian

AU - García-Miñaúr, Sixto

AU - Fernández, Luis

AU - Antonarakis, Stylianos E.

AU - Biondi, Massimo

AU - Boot, Erik

AU - Breetvelt, Elemi

AU - Busa, Tiffany

AU - Butcher, Nancy

AU - Buzzanca, Antonino

AU - Carmel, Miri

AU - Cleynen, Isabelle

AU - Cutler, David

AU - Dallapiccola, Bruno

AU - de la Fuente Sanches, María Angeles

AU - Epstein, Michael P.

AU - Evers, Rens

AU - Fernandez, Luis

AU - Fritsch, Rosemarie

N1 - Funding Information: We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577, R01HL084410, U01MH101720, U54HD090260, and P01HD070454. Other funding sources are detailed in the Supplemental Information. Funding Information: We would like to thank the 22q11.2DS-affected families who provided DNA and clinical information for this study. We acknowledge the Genomics and Molecular Cytogenetics Cores at the Albert Einstein College of Medicine. We thank the Pediatric Cardiac Genomics Consortium for data collection and management and for the use of published data, without which the replication of the findings in our 22q11.2DS cohort in CTD cohorts without a 22q11.2 deletion would have never been possible. Dr. Morrow was supported by a Leducq Foundation grant and National Institutes of Health grants R01HL132577 , R01HL084410 , U01MH101720 , U54HD090260 , and P01HD070454 . Other funding sources are detailed in the Supplemental Information . Publisher Copyright: © 2019 American Society of Human Genetics

PY - 2020/1/2

Y1 - 2020/1/2

N2 - 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.

AB - 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.

KW - CRKL

KW - DiGeorge syndrome

KW - TBX1

KW - chromosome 22q11.2 deletion syndrome

KW - complex trait

KW - congenital heart disease

KW - conotruncal heart defects

KW - copy number variation

KW - genetic association

KW - genetic modifier

KW - haploinsufficiency

UR - http://www.scopus.com/inward/record.url?scp=85077046877&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2019.11.010

DO - 10.1016/j.ajhg.2019.11.010

M3 - Article

AN - SCOPUS:85077046877

SN - 0002-9297

VL - 106

SP - 26

EP - 40

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this