Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Wolfram Demaerel; Matthew S. Hestand; Elfi Vergaelen; Ann Swillen; Marcos López-Sánchez; Luis A. Pérez-Jurado; Donna M. McDonald-Mcginn; Elaine Zackai; Beverly S. Emanuel; Bernice E. Morrow; Jeroen Breckpot; Koenraad Devriendt; Joris R. Vermeesch; Kevin M. Antshel; Celso Arango; Marco Armando; Anne S. Bassett; Carrie E. Bearden; Erik Boot; Marta Bravo-Sanchez; Elemi Breetvelt; Tiffany Busa; Nancy J. Butcher; Linda E. Campbell; Miri Carmel; Eva W C Chow; T. Blaine Crowley; Joseph Cubells; David Cutler; Wolfram Demaerel; Maria Cristina Digilio; Sasja Duijff; Stephan Eliez; Beverly S. Emanuel; Michael P. Epstein; Rens Evers; Luis Fernandez Garcia-Moya; Ania Fiksinski; David Fraguas; Wanda Fremont; Rosemarie Fritsch; Sixto Garcia-Minaur; Aaron Golden; Doron Gothelf; Tingwei Guo; Ruben C. Gur; Raquel E. Gur; Damian Heine-Suner; Matthew Hestand; Jacob Vorstman

doi:10.1016/j.ajhg.2017.09.002

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Wolfram Demaerel, Matthew S. Hestand, Elfi Vergaelen, Ann Swillen, Marcos López-Sánchez, Luis A. Pérez-Jurado, Donna M. McDonald-Mcginn, Elaine Zackai, Beverly S. Emanuel, Bernice E. Morrow, Jeroen Breckpot, Koenraad Devriendt, Joris R. Vermeesch, Kevin M. Antshel, Celso Arango, Marco Armando, Anne S. Bassett, Carrie E. Bearden, Erik Boot, Marta Bravo-SanchezElemi Breetvelt, Tiffany Busa, Nancy J. Butcher, Linda E. Campbell, Miri Carmel, Eva W C Chow, T. Blaine Crowley, Joseph Cubells, David Cutler, Wolfram Demaerel, Maria Cristina Digilio, Sasja Duijff, Stephan Eliez, Beverly S. Emanuel, Michael P. Epstein, Rens Evers, Luis Fernandez Garcia-Moya, Ania Fiksinski, David Fraguas, Wanda Fremont, Rosemarie Fritsch, Sixto Garcia-Minaur, Aaron Golden, Doron Gothelf, Tingwei Guo, Ruben C. Gur, Raquel E. Gur, Damian Heine-Suner, Matthew Hestand, Jacob Vorstman,

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

Abstract

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

Original language	English
Pages (from-to)	616-622
Number of pages	7
Journal	American Journal of Human Genetics
Volume	101
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2017.09.002
Publication status	Published - 5 Oct 2017

Keywords

22q11.2 deletion syndrome
22q11.2DS
DiGeorge syndrome
fiber-FISH
Genomic disorder
inversion polymorphism
low-copy repeats
microdeletion
segmental duplications
VCFS

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10.1016/j.ajhg.2017.09.002

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Demaerel, W., Hestand, M. S., Vergaelen, E., Swillen, A., López-Sánchez, M., Pérez-Jurado, L. A., McDonald-Mcginn, D. M., Zackai, E., Emanuel, B. S., Morrow, B. E., Breckpot, J., Devriendt, K., Vermeesch, J. R., Antshel, K. M., Arango, C., Armando, M., Bassett, A. S., Bearden, C. E., Boot, E. (2017). Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements. American Journal of Human Genetics, 101(4), 616-622. https://doi.org/10.1016/j.ajhg.2017.09.002

@article{3be38e978d74434abbd6f05d02f27f10,

title = "Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements",

abstract = "Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.",

keywords = "22q11.2 deletion syndrome, 22q11.2DS, DiGeorge syndrome, fiber-FISH, Genomic disorder, inversion polymorphism, low-copy repeats, microdeletion, segmental duplications, VCFS",

author = "Wolfram Demaerel and Hestand, {Matthew S.} and Elfi Vergaelen and Ann Swillen and Marcos L{\'o}pez-S{\'a}nchez and P{\'e}rez-Jurado, {Luis A.} and McDonald-Mcginn, {Donna M.} and Elaine Zackai and Emanuel, {Beverly S.} and Morrow, {Bernice E.} and Jeroen Breckpot and Koenraad Devriendt and Vermeesch, {Joris R.} and Antshel, {Kevin M.} and Celso Arango and Marco Armando and Bassett, {Anne S.} and Bearden, {Carrie E.} and Erik Boot and Marta Bravo-Sanchez and Elemi Breetvelt and Tiffany Busa and Butcher, {Nancy J.} and Campbell, {Linda E.} and Miri Carmel and Chow, {Eva W C} and Crowley, {T. Blaine} and Joseph Cubells and David Cutler and Wolfram Demaerel and Digilio, {Maria Cristina} and Sasja Duijff and Stephan Eliez and Emanuel, {Beverly S.} and Epstein, {Michael P.} and Rens Evers and {Fernandez Garcia-Moya}, Luis and Ania Fiksinski and David Fraguas and Wanda Fremont and Rosemarie Fritsch and Sixto Garcia-Minaur and Aaron Golden and Doron Gothelf and Tingwei Guo and Gur, {Ruben C.} and Gur, {Raquel E.} and Damian Heine-Suner and Matthew Hestand and Jacob Vorstman",

note = "Funding Information: W.D. is a fellow at KU Leuven and is supported by IWT ( 131625 ). This work was made possible by grants from the KUL PFV/10/016 SymBioSys to J.R.V. and GOA/12/015 to J.R.V. and K.D, the FWO to J.V. ( G.0E1117N ), the National Institute of Mental Health ( 5U01MH101723-02 ), and the Belgian Science Policy Office Interuniversity Attraction Poles ( BELSPO-IAP ) program through the project IAP P7/43-BeMGI. L.A.P.J.{\textquoteright}s lab was funded by the Marat{\'o} de TV3 ( 20153230 ), the Spanish Ministry of Economy and Competitiveness ( Pi1302481 ), and the Catalan Department of Economy and Knowledge ( 2014SGR1468 and the ICREA Acad{\`e}mia award). J.V.R. was funded by the Jerome Lejeune Foundation (project # 1665 ). The molar cell lines CHM1 and CHM13 were kindly provided by E. Eichler. D.M.M.-M has given lectures for Natera on 22q11.2 deletion syndrome. L.A.P.J. is a scientific advisor of qGenomics Laboratory, S.L.. Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = oct,

day = "5",

doi = "10.1016/j.ajhg.2017.09.002",

language = "English",

volume = "101",

pages = "616--622",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Demaerel, W, Hestand, MS, Vergaelen, E, Swillen, A, López-Sánchez, M, Pérez-Jurado, LA, McDonald-Mcginn, DM, Zackai, E, Emanuel, BS, Morrow, BE, Breckpot, J, Devriendt, K, Vermeesch, JR, Antshel, KM, Arango, C, Armando, M, Bassett, AS, Bearden, CE, Boot, E, Bravo-Sanchez, M, Breetvelt, E, Busa, T, Butcher, NJ, Campbell, LE, Carmel, M, Chow, EWC, Crowley, TB, Cubells, J, Cutler, D, Demaerel, W, Digilio, MC, Duijff, S, Eliez, S, Emanuel, BS, Epstein, MP, Evers, R, Fernandez Garcia-Moya, L, Fiksinski, A, Fraguas, D, Fremont, W, Fritsch, R, Garcia-Minaur, S, Golden, A, Gothelf, D, Guo, T, Gur, RC, Gur, RE, Heine-Suner, D, Hestand, M, Vorstman, J 2017, 'Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements', American Journal of Human Genetics, vol. 101, no. 4, pp. 616-622. https://doi.org/10.1016/j.ajhg.2017.09.002

TY - JOUR

T1 - Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

AU - Demaerel, Wolfram

AU - Hestand, Matthew S.

AU - Vergaelen, Elfi

AU - Swillen, Ann

AU - López-Sánchez, Marcos

AU - Pérez-Jurado, Luis A.

AU - McDonald-Mcginn, Donna M.

AU - Zackai, Elaine

AU - Emanuel, Beverly S.

AU - Morrow, Bernice E.

AU - Breckpot, Jeroen

AU - Devriendt, Koenraad

AU - Vermeesch, Joris R.

AU - Antshel, Kevin M.

AU - Arango, Celso

AU - Armando, Marco

AU - Bassett, Anne S.

AU - Bearden, Carrie E.

AU - Boot, Erik

AU - Bravo-Sanchez, Marta

AU - Breetvelt, Elemi

AU - Busa, Tiffany

AU - Butcher, Nancy J.

AU - Campbell, Linda E.

AU - Carmel, Miri

AU - Chow, Eva W C

AU - Crowley, T. Blaine

AU - Cubells, Joseph

AU - Cutler, David

AU - Demaerel, Wolfram

AU - Digilio, Maria Cristina

AU - Duijff, Sasja

AU - Eliez, Stephan

AU - Emanuel, Beverly S.

AU - Epstein, Michael P.

AU - Evers, Rens

AU - Fernandez Garcia-Moya, Luis

AU - Fiksinski, Ania

AU - Fraguas, David

AU - Fremont, Wanda

AU - Fritsch, Rosemarie

AU - Garcia-Minaur, Sixto

AU - Golden, Aaron

AU - Gothelf, Doron

AU - Guo, Tingwei

AU - Gur, Ruben C.

AU - Gur, Raquel E.

AU - Heine-Suner, Damian

AU - Hestand, Matthew

AU - Vorstman, Jacob

N1 - Funding Information: W.D. is a fellow at KU Leuven and is supported by IWT ( 131625 ). This work was made possible by grants from the KUL PFV/10/016 SymBioSys to J.R.V. and GOA/12/015 to J.R.V. and K.D, the FWO to J.V. ( G.0E1117N ), the National Institute of Mental Health ( 5U01MH101723-02 ), and the Belgian Science Policy Office Interuniversity Attraction Poles ( BELSPO-IAP ) program through the project IAP P7/43-BeMGI. L.A.P.J.’s lab was funded by the Marató de TV3 ( 20153230 ), the Spanish Ministry of Economy and Competitiveness ( Pi1302481 ), and the Catalan Department of Economy and Knowledge ( 2014SGR1468 and the ICREA Acadèmia award). J.V.R. was funded by the Jerome Lejeune Foundation (project # 1665 ). The molar cell lines CHM1 and CHM13 were kindly provided by E. Eichler. D.M.M.-M has given lectures for Natera on 22q11.2 deletion syndrome. L.A.P.J. is a scientific advisor of qGenomics Laboratory, S.L.. Publisher Copyright: © 2017

PY - 2017/10/5

Y1 - 2017/10/5

N2 - Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

AB - Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

KW - 22q11.2 deletion syndrome

KW - 22q11.2DS

KW - DiGeorge syndrome

KW - fiber-FISH

KW - Genomic disorder

KW - inversion polymorphism

KW - low-copy repeats

KW - microdeletion

KW - segmental duplications

KW - VCFS

UR - http://www.scopus.com/inward/record.url?scp=85030694733&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.09.002

DO - 10.1016/j.ajhg.2017.09.002

M3 - Article

C2 - 28965848

AN - SCOPUS:85030694733

SN - 0002-9297

VL - 101

SP - 616

EP - 622

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

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