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

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

doi:10.1038/ng.534

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

Santhosh Girirajan, Jill Rosenfeld, Gregory Cooper, Francesca Antonacci, Priscilla Siswara, Andy Itsara, Laura Vives, Tom Walsh, Shane McCarthy, Carl Baker, Heather Mefford, Jeffrey Kidd, Sharon Browning, Brian Browning, Diane Dickel, Deborah Levy, Blake Ballif, Kathryn Platky, Darren Farber, Gordon GowansJessica Wetherbee, Alexander Asamoah, David Weaver, Paul Mark, Jennifer Dickerson, Bhuwan Garg, Sara Ellingwood, Rosemarie Smith, Valerie Banks, Wendy Smith, Marie McDonald, Joe Hoo, Beatrice French, Cindy Hudson, John Johnson, Jillian Ozmore, John Moeschler, Urvashi Surti, Luis Escobar, Dima El-Khechen, Jerome Gorski, Jennifer Kussman, Bonnie Salbert, Yves Lacassie, Alisha Biser, Donna McDonald-McGinn, Elaine Zackai, Matthew Deardorff, Tamim Shaikh, Eric Haan, K Friend, Marco Fichera, Corrado Romano, J Gecz, Lynn DeLisi, Jonathan Sebat, Mary-Claire King, Lisa Shaffer, Evan 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
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
Publication status	Published - Mar 2010

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Girirajan, S., Rosenfeld, J., Cooper, G., Antonacci, F., Siswara, P., Itsara, A., Vives, L., Walsh, T., McCarthy, S., Baker, C., Mefford, H., Kidd, J., Browning, S., Browning, B., Dickel, D., Levy, D., Ballif, B., Platky, K., Farber, D., ... Eichler, 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{3647b008358b4eca8e1f0e19f9b77583,

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 Jill Rosenfeld and Gregory Cooper and Francesca Antonacci and Priscilla Siswara and Andy Itsara and Laura Vives and Tom Walsh and Shane McCarthy and Carl Baker and Heather Mefford and Jeffrey Kidd and Sharon Browning and Brian Browning and Diane Dickel and Deborah Levy and Blake Ballif and Kathryn Platky and Darren Farber and Gordon Gowans and Jessica Wetherbee and Alexander Asamoah and David Weaver and Paul Mark and Jennifer Dickerson and Bhuwan Garg and Sara Ellingwood and Rosemarie Smith and Valerie Banks and Wendy Smith and Marie McDonald and Joe Hoo and Beatrice French and Cindy Hudson and John Johnson and Jillian Ozmore and John Moeschler and Urvashi Surti and Luis Escobar and Dima El-Khechen and Jerome Gorski and Jennifer Kussman and Bonnie Salbert and Yves Lacassie and Alisha Biser and Donna McDonald-McGinn and Elaine Zackai and Matthew Deardorff and Tamim Shaikh and Eric Haan and K Friend and Marco Fichera and Corrado Romano and J Gecz and Lynn DeLisi and Jonathan Sebat and Mary-Claire King and Lisa Shaffer and Evan Eichler",

year = "2010",

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doi = "10.1038/ng.534",

language = "English",

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pages = "203--209",

journal = "Nature Genetics",

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Girirajan, S, Rosenfeld, J, Cooper, G, Antonacci, F, Siswara, P, Itsara, A, Vives, L, Walsh, T, McCarthy, S, Baker, C, Mefford, H, Kidd, J, Browning, S, Browning, B, Dickel, D, Levy, D, Ballif, B, Platky, K, Farber, D, Gowans, G, Wetherbee, J, Asamoah, A, Weaver, D, Mark, P, Dickerson, J, Garg, B, Ellingwood, S, Smith, R, Banks, V, Smith, W, McDonald, M, Hoo, J, French, B, Hudson, C, Johnson, J, Ozmore, J, Moeschler, J, Surti, U, Escobar, L, El-Khechen, D, Gorski, J, Kussman, J, Salbert, B, Lacassie, Y, Biser, A, McDonald-McGinn, D, Zackai, E, Deardorff, M, Shaikh, T, Haan, E, Friend, K, Fichera, M, Romano, C, Gecz, J, DeLisi, L, Sebat, J, King, M-C, Shaffer, L & Eichler, E 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

AU - Cooper, Gregory

AU - Antonacci, Francesca

AU - Siswara, Priscilla

AU - Itsara, Andy

AU - Vives, Laura

AU - Walsh, Tom

AU - McCarthy, Shane

AU - Baker, Carl

AU - Mefford, Heather

AU - Kidd, Jeffrey

AU - Browning, Sharon

AU - Browning, Brian

AU - Dickel, Diane

AU - Levy, Deborah

AU - Ballif, Blake

AU - Platky, Kathryn

AU - Farber, Darren

AU - Gowans, Gordon

AU - Wetherbee, Jessica

AU - Asamoah, Alexander

AU - Weaver, David

AU - Mark, Paul

AU - Dickerson, Jennifer

AU - Garg, Bhuwan

AU - Ellingwood, Sara

AU - Smith, Rosemarie

AU - Banks, Valerie

AU - Smith, Wendy

AU - McDonald, Marie

AU - Hoo, Joe

AU - French, Beatrice

AU - Hudson, Cindy

AU - Johnson, John

AU - Ozmore, Jillian

AU - Moeschler, John

AU - Surti, Urvashi

AU - Escobar, Luis

AU - El-Khechen, Dima

AU - Gorski, Jerome

AU - Kussman, Jennifer

AU - Salbert, Bonnie

AU - Lacassie, Yves

AU - Biser, Alisha

AU - McDonald-McGinn, Donna

AU - Zackai, Elaine

AU - Deardorff, Matthew

AU - Shaikh, Tamim

AU - Haan, Eric

AU - Friend, K

AU - Fichera, Marco

AU - Romano, Corrado

AU - Gecz, J

AU - DeLisi, Lynn

AU - Sebat, Jonathan

AU - King, Mary-Claire

AU - Shaffer, Lisa

AU - Eichler, Evan

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

U2 - 10.1038/ng.534

DO - 10.1038/ng.534

M3 - Article

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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