A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Santhosh Girirajan; Jill A. Rosenfeld; Gregory M. Cooper; Francesca Antonacci; Priscillia Siswara; Andy Itsara; Laura Vives; Tom Walsh; Shane E. McCarthy; Carl Baker; Heather C. Mefford; Jeffrey M. Kidd; Sharon R. Browning; Brian L. Browning; Diane E. Dickel; Deborah L. Levy; Blake C. Ballif; Kathryn Platky; Darren M. Farber; Gordon C. Gowans; Jessica J. Wetherbee; Alexander Asamoah; David D. Weaver; Paul R. Mark; Jennifer Dickerson; Bhuwan P. Garg; Sara A. Ellingwood; Rosemarie Smith; Valerie C. Banks; Wendy Smith; Marie T. McDonald; Joe J. Hoo; Beatrice N. French; Cindy Hudson; John P. Johnson; Jillian R. Ozmore; John B. Moeschler; Urvashi Surti; Luis F. Escobar; Dima El-Khechen; Jerome L. Gorski; Jennifer Kussmann; Bonnie Salbert; Yves Lacassie; Alisha Biser; Donna M. McDonald-Mcginn; Elaine H. Zackai; Matthew A. Deardorff; Tamim H. Shaikh; Eric Haan; Kathryn L. Friend; Marco Fichera; Corrado Romano; Jozef Gécz; Lynn E. Delisi; Jonathan Sebat; Mary Claire King; Lisa G. Shaffer; Evan E. Eichler

doi:10.1038/ng.534

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Santhosh Girirajan, Jill A. Rosenfeld, Gregory M. Cooper, Francesca Antonacci, Priscillia Siswara, Andy Itsara, Laura Vives, Tom Walsh, Shane E. McCarthy, Carl Baker, Heather C. Mefford, Jeffrey M. Kidd, Sharon R. Browning, Brian L. Browning, Diane E. Dickel, Deborah L. Levy, Blake C. Ballif, Kathryn Platky, Darren M. Farber, Gordon C. GowansJessica J. Wetherbee, Alexander Asamoah, David D. Weaver, Paul R. Mark, Jennifer Dickerson, Bhuwan P. Garg, Sara A. Ellingwood, Rosemarie Smith, Valerie C. Banks, Wendy Smith, Marie T. McDonald, Joe J. Hoo, Beatrice N. French, Cindy Hudson, John P. Johnson, Jillian R. Ozmore, John B. Moeschler, Urvashi Surti, Luis F. Escobar, Dima El-Khechen, Jerome L. Gorski, Jennifer Kussmann, Bonnie Salbert, Yves Lacassie, Alisha Biser, Donna M. McDonald-Mcginn, Elaine H. Zackai, Matthew A. Deardorff, Tamim H. Shaikh, Eric Haan, Kathryn L. Friend, Marco Fichera, Corrado Romano, Jozef Gécz, Lynn E. Delisi, Jonathan Sebat, Mary Claire King, Lisa G. Shaffer, Evan E. Eichler

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Abstract

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10 5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Original language	English (US)
Pages (from-to)	203-209
Number of pages	7
Journal	Nature Genetics
Volume	42
Issue number	3
DOIs	https://doi.org/10.1038/ng.534
State	Published - Mar 2010

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/ng.534

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Girirajan, S., Rosenfeld, J. A., Cooper, G. M., Antonacci, F., Siswara, P., Itsara, A., Vives, L., Walsh, T., McCarthy, S. E., Baker, C., Mefford, H. C., Kidd, J. M., Browning, S. R., Browning, B. L., Dickel, D. E., Levy, D. L., Ballif, B. C., Platky, K., Farber, D. M., ... Eichler, E. E. (2010). A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 42(3), 203-209. https://doi.org/10.1038/ng.534

@article{cd726b6cb16d4881876d468039ffa81e,

title = "A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay",

abstract = "We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10 5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.",

author = "Santhosh Girirajan and Rosenfeld, {Jill A.} and Cooper, {Gregory M.} and Francesca Antonacci and Priscillia Siswara and Andy Itsara and Laura Vives and Tom Walsh and McCarthy, {Shane E.} and Carl Baker and Mefford, {Heather C.} and Kidd, {Jeffrey M.} and Browning, {Sharon R.} and Browning, {Brian L.} and Dickel, {Diane E.} and Levy, {Deborah L.} and Ballif, {Blake C.} and Kathryn Platky and Farber, {Darren M.} and Gowans, {Gordon C.} and Wetherbee, {Jessica J.} and Alexander Asamoah and Weaver, {David D.} and Mark, {Paul R.} and Jennifer Dickerson and Garg, {Bhuwan P.} and Ellingwood, {Sara A.} and Rosemarie Smith and Banks, {Valerie C.} and Wendy Smith and McDonald, {Marie T.} and Hoo, {Joe J.} and French, {Beatrice N.} and Cindy Hudson and Johnson, {John P.} and Ozmore, {Jillian R.} and Moeschler, {John B.} and Urvashi Surti and Escobar, {Luis F.} and Dima El-Khechen and Gorski, {Jerome L.} and Jennifer Kussmann and Bonnie Salbert and Yves Lacassie and Alisha Biser and McDonald-Mcginn, {Donna M.} and Zackai, {Elaine H.} and Deardorff, {Matthew A.} and Shaikh, {Tamim H.} and Eric Haan and Friend, {Kathryn L.} and Marco Fichera and Corrado Romano and Jozef G{\'e}cz and Delisi, {Lynn E.} and Jonathan Sebat and King, {Mary Claire} and Shaffer, {Lisa G.} and Eichler, {Evan E.}",

note = "Funding Information: for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator: P.V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA). We also thank J. Smith for SNP genotyping; T. Louie for bioinformatics support; C. Campbell, L. Perez-Jurado, G. Kirov, M.K. Rudd and C. Lese-Martin for useful discussions; and T. Brown, P. Sudmant and J. Kitzman for critical review of the manuscript. This work was supported by NIH grant HD065285 (E.E.E.), a grant from the Simons Foundation (SFARI 137578 to E.E.E.) and a NARSAD Award (M.-C.K.). G.M.C. is supported by a Merck, Jane Coffin Childs Memorial Fund post-doctoral fellowship. E.E.E. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank the subjects and their families for participating in this study. We thank M. Whyte for providing cardiological evaluation (for case SG07). We thank A. Singleton, L. Ferrucci and R. Krauss for sharing the control CNV data generated with support from the Intramural Research Program of the National Institute on Aging, National Heart, Lung, and Blood Institute (PARC project), and the National Institutes of Health, Department of Health and Human Services. For the schizophrenia study, genotyping of samples was also provided through the genetic association information network (GAIN). Samples and associated phenotype data",

year = "2010",

month = mar,

doi = "10.1038/ng.534",

language = "English (US)",

volume = "42",

pages = "203--209",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

Girirajan, S, Rosenfeld, JA, Cooper, GM, Antonacci, F, Siswara, P, Itsara, A, Vives, L, Walsh, T, McCarthy, SE, Baker, C, Mefford, HC, Kidd, JM, Browning, SR, Browning, BL, Dickel, DE, Levy, DL, Ballif, BC, Platky, K, Farber, DM, Gowans, GC, Wetherbee, JJ, Asamoah, A, Weaver, DD, Mark, PR, Dickerson, J, Garg, BP, Ellingwood, SA, Smith, R, Banks, VC, Smith, W, McDonald, MT, Hoo, JJ, French, BN, Hudson, C, Johnson, JP, Ozmore, JR, Moeschler, JB, Surti, U, Escobar, LF, El-Khechen, D, Gorski, JL, Kussmann, J, Salbert, B, Lacassie, Y, Biser, A, McDonald-Mcginn, DM, Zackai, EH, Deardorff, MA, Shaikh, TH, Haan, E, Friend, KL, Fichera, M, Romano, C, Gécz, J, Delisi, LE, Sebat, J, King, MC, Shaffer, LG & Eichler, EE 2010, 'A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay', Nature Genetics, vol. 42, no. 3, pp. 203-209. https://doi.org/10.1038/ng.534

TY - JOUR

T1 - A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

AU - Girirajan, Santhosh

AU - Rosenfeld, Jill A.

AU - Cooper, Gregory M.

AU - Antonacci, Francesca

AU - Siswara, Priscillia

AU - Itsara, Andy

AU - Vives, Laura

AU - Walsh, Tom

AU - McCarthy, Shane E.

AU - Baker, Carl

AU - Mefford, Heather C.

AU - Kidd, Jeffrey M.

AU - Browning, Sharon R.

AU - Browning, Brian L.

AU - Dickel, Diane E.

AU - Levy, Deborah L.

AU - Ballif, Blake C.

AU - Platky, Kathryn

AU - Farber, Darren M.

AU - Gowans, Gordon C.

AU - Wetherbee, Jessica J.

AU - Asamoah, Alexander

AU - Weaver, David D.

AU - Mark, Paul R.

AU - Dickerson, Jennifer

AU - Garg, Bhuwan P.

AU - Ellingwood, Sara A.

AU - Smith, Rosemarie

AU - Banks, Valerie C.

AU - Smith, Wendy

AU - McDonald, Marie T.

AU - Hoo, Joe J.

AU - French, Beatrice N.

AU - Hudson, Cindy

AU - Johnson, John P.

AU - Ozmore, Jillian R.

AU - Moeschler, John B.

AU - Surti, Urvashi

AU - Escobar, Luis F.

AU - El-Khechen, Dima

AU - Gorski, Jerome L.

AU - Kussmann, Jennifer

AU - Salbert, Bonnie

AU - Lacassie, Yves

AU - Biser, Alisha

AU - McDonald-Mcginn, Donna M.

AU - Zackai, Elaine H.

AU - Deardorff, Matthew A.

AU - Shaikh, Tamim H.

AU - Haan, Eric

AU - Friend, Kathryn L.

AU - Fichera, Marco

AU - Romano, Corrado

AU - Gécz, Jozef

AU - Delisi, Lynn E.

AU - Sebat, Jonathan

AU - King, Mary Claire

AU - Shaffer, Lisa G.

AU - Eichler, Evan E.

N1 - Funding Information: for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator: P.V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA). We also thank J. Smith for SNP genotyping; T. Louie for bioinformatics support; C. Campbell, L. Perez-Jurado, G. Kirov, M.K. Rudd and C. Lese-Martin for useful discussions; and T. Brown, P. Sudmant and J. Kitzman for critical review of the manuscript. This work was supported by NIH grant HD065285 (E.E.E.), a grant from the Simons Foundation (SFARI 137578 to E.E.E.) and a NARSAD Award (M.-C.K.). G.M.C. is supported by a Merck, Jane Coffin Childs Memorial Fund post-doctoral fellowship. E.E.E. is an investigator of the Howard Hughes Medical Institute. Funding Information: We thank the subjects and their families for participating in this study. We thank M. Whyte for providing cardiological evaluation (for case SG07). We thank A. Singleton, L. Ferrucci and R. Krauss for sharing the control CNV data generated with support from the Intramural Research Program of the National Institute on Aging, National Heart, Lung, and Blood Institute (PARC project), and the National Institutes of Health, Department of Health and Human Services. For the schizophrenia study, genotyping of samples was also provided through the genetic association information network (GAIN). Samples and associated phenotype data

PY - 2010/3

Y1 - 2010/3

N2 - We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10 5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

AB - We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10 5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

UR - http://www.scopus.com/inward/record.url?scp=77649122250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77649122250&partnerID=8YFLogxK

U2 - 10.1038/ng.534

DO - 10.1038/ng.534

M3 - Article

C2 - 20154674

AN - SCOPUS:77649122250

SN - 1061-4036

VL - 42

SP - 203

EP - 209

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

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