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

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; Stylianos E. Antonarakis; Massimo Biondi; Erik Boot; Elemi Breetvelt; Tiffany Busa; Nancy Butcher; Antonino Buzzanca; Miri Carmel; Isabelle Cleynen; David Cutler; Bruno Dallapiccola; María Angeles de la Fuente Sanches; Michael P. Epstein; Rens Evers; Guido Lattanzi

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

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 BreeHayley 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, Stylianos E. Antonarakis, Massimo Biondi, Erik Boot, Elemi Breetvelt, Tiffany Busa, Nancy Butcher, Antonino Buzzanca, Miri Carmel, Isabelle Cleynen, David Cutler, Bruno Dallapiccola, María Angeles de la Fuente Sanches, Michael P. Epstein, Rens Evers, Guido Lattanzi

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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
Publication status	Published - 2 Jan 2020

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2019.11.010

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Zhao, Y., Diacou, A., Johnston, H. R., Musfee, F. I., McDonald-McGinn, D. M., McGinn, D., Crowley, T. B., Repetto, G. M., Swillen, A., Breckpot, J., Vermeesch, J. R., Kates, W. R., Digilio, M. C., Unolt, M., Marino, B., Pontillo, M., Armando, M., Di Fabio, F., Vicari, S., ... Lattanzi, G. (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, 106(1), 26-40. https://doi.org/10.1016/j.ajhg.2019.11.010

@article{15b65af5bef14601876e54d1d9b9c9d3,

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

author = "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 Guido Lattanzi",

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 = "Elsevier",

number = "1",

}

Zhao, Y, 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, F, 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 & Lattanzi, G 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. https://doi.org/10.1016/j.ajhg.2019.11.010

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 - 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 - Lattanzi, Guido

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 - chromosome 22q11.2 deletion syndrome

KW - complex trait

KW - congenital heart disease

KW - conotruncal heart defects

KW - copy number variation

KW - CRKL

KW - DiGeorge syndrome

KW - genetic association

KW - genetic modifier

KW - haploinsufficiency

KW - TBX1

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

C2 - 31870554

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

Keywords

UN SDGs

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