The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Claire Redin; Harrison Brand; Ryan L. Collins; Tammy Kammin; Elyse Mitchell; Jennelle C. Hodge; Carrie Hanscom; Vamsee Pillalamarri; Catarina M. Seabra; Mary-Alice Abbott; Omar A. Abdul-Rahman; Erika Aberg; Rhett Adley; Sofia L. Alcaraz-Estrada; Fowzan S. Alkuraya; Yu An; Mary-Anne Anderson; Caroline Antolik; Kwame Anyane-Yeboa; Joan F. Atkin; Tina Bartell; Jonathan A. Bernstein; Elizabeth Beyer; Ian Blumenthal; Ernie M. H. F. Bongers; Eva H. Brilstra; Chester W. Brown; Hennie T. Bruggenwirth; Bert Callewaert; Colby Chiang; Ken Corning; Helen Cox; Edwin Cuppen; Benjamin B. Currall; Tom Cushing; Dezso David; Matthew A. Deardorff; Annelies Dheedene; Marc D'Hooghe; Bert B. A. de Vries; Dawn L. Earl; Heather L. Ferguson; Heather Fisher; David R. FitzPatrick; Pamela Gerrol; Daniela Giachino; Joseph T. Glessner; Troy Gliem; Margo Grady; Brett H. Graham; Cristin Griffis; Karen W. Gripp; Andrea L. Gropman; Andrea Hanson-Kahn; David J. Harris; Mark A. Hayden; Rosamund Hill; Ron Hochstenbach; Jodi D. Hoffman; Robert J. Hopkin; Monika W. Hubshman; A. Micheil Innes; Mira Irons; Melita Irving; Jessie C. Jacobsen; Sandra Janssens; Tamison Jewett; John P. Johnson; Marjolijn C. Jongmans; Stephen G. Kahler; David A. Koolen; Jerome Korzelius; Peter M. Kroisel; Yves Lacassie; William Lawless; Emmanuelle Lemyre; Kathleen Leppig; Alex V. Levin; Haibo Li; Hong Li; Eric C. Liao; Cynthia Lim; Edward J. Lose; Diane Lucente; Michael J. Macera; Poornima Manavalan; Giorgia Mandrile; Carlo L. Marcelis; Lauren Margolin; Tamara Mason; Diane Masser-Frye; Michael W. McClellan; Cinthya J. Zepeda Mendoza; Bjorn Menten; Sjors Middelkamp; Liya R. Mikami; Emily Moe; Shehla Mohammed; Tarja Mononen; Megan E. Mortenson; Graciela Moya; Aggie W. Nieuwint; Zehra Ordulu; Sandhya Parkash; Susan P. Pauker; Shahrin Pereira; Danielle Perrin; Katy Phelan; Raul E. Pina Aguilar; Pino J. Poddighe; Giulia Pregno; Salmo Raskin; Linda Reis; William Rhead; Debra Rita; Ivo Renkens; Filip Roelens; Jayla Ruliera; Patrick Rump; Samantha L. P. Schilit; Ranad Shaheen; Rebecca Sparkes; Erica Spiegel; Blair Stevens; Matthew R. Stone; Julia Tagoe; Joseph V. Thakuria; Bregje W. van Bon; Jiddeke van de Kamp; Ineke van Der Burgt; Ton van Essen; Conny M. van Ravenswaaij-Arts; Markus J. van Roosmalen; Sarah Vergult; Catharina M. L. Volker-Touw; Dorothy P. Warburton; Matthew J. Waterman; Susan Wiley; Anna Wilson; Maria de la Concepcion A. Yerena-de Vega; Roberto T. Zori; Brynn Levy; Han G. Brunner; Nicole de Leeuw; Wigard P. Kloosterman; Erik C. Thorland; Cynthia C. Morton; James F. Gusella; Michael E. Talkowski

doi:10.1038/ng.3720

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Claire Redin, Harrison Brand, Ryan L. Collins, Tammy Kammin, Elyse Mitchell, Jennelle C. Hodge, Carrie Hanscom, Vamsee Pillalamarri, Catarina M. Seabra, Mary-Alice Abbott, Omar A. Abdul-Rahman, Erika Aberg, Rhett Adley, Sofia L. Alcaraz-Estrada, Fowzan S. Alkuraya, Yu An, Mary-Anne Anderson, Caroline Antolik, Kwame Anyane-Yeboa, Joan F. AtkinTina Bartell, Jonathan A. Bernstein, Elizabeth Beyer, Ian Blumenthal, Ernie M. H. F. Bongers, Eva H. Brilstra, Chester W. Brown, Hennie T. Bruggenwirth, Bert Callewaert, Colby Chiang, Ken Corning, Helen Cox, Edwin Cuppen, Benjamin B. Currall, Tom Cushing, Dezso David, Matthew A. Deardorff, Annelies Dheedene, Marc D'Hooghe, Bert B. A. de Vries, Dawn L. Earl, Heather L. Ferguson, Heather Fisher, David R. FitzPatrick, Pamela Gerrol, Daniela Giachino, Joseph T. Glessner, Troy Gliem, Margo Grady, Brett H. Graham, Cristin Griffis, Karen W. Gripp, Andrea L. Gropman, Andrea Hanson-Kahn, David J. Harris, Mark A. Hayden, Rosamund Hill, Ron Hochstenbach, Jodi D. Hoffman, Robert J. Hopkin, Monika W. Hubshman, A. Micheil Innes, Mira Irons, Melita Irving, Jessie C. Jacobsen, Sandra Janssens, Tamison Jewett, John P. Johnson, Marjolijn C. Jongmans, Stephen G. Kahler, David A. Koolen, Jerome Korzelius, Peter M. Kroisel, Yves Lacassie, William Lawless, Emmanuelle Lemyre, Kathleen Leppig, Alex V. Levin, Haibo Li, Hong Li, Eric C. Liao, Cynthia Lim, Edward J. Lose, Diane Lucente, Michael J. Macera, Poornima Manavalan, Giorgia Mandrile, Carlo L. Marcelis, Lauren Margolin, Tamara Mason, Diane Masser-Frye, Michael W. McClellan, Cinthya J. Zepeda Mendoza, Bjorn Menten, Sjors Middelkamp, Liya R. Mikami, Emily Moe, Shehla Mohammed, Tarja Mononen, Megan E. Mortenson, Graciela Moya, Aggie W. Nieuwint, Zehra Ordulu, Sandhya Parkash, Susan P. Pauker, Shahrin Pereira, Danielle Perrin, Katy Phelan, Raul E. Pina Aguilar, Pino J. Poddighe, Giulia Pregno, Salmo Raskin, Linda Reis, William Rhead, Debra Rita, Ivo Renkens, Filip Roelens, Jayla Ruliera, Patrick Rump, Samantha L. P. Schilit, Ranad Shaheen, Rebecca Sparkes, Erica Spiegel, Blair Stevens, Matthew R. Stone, Julia Tagoe, Joseph V. Thakuria, Bregje W. van Bon, Jiddeke van de Kamp, Ineke van Der Burgt, Ton van Essen, Conny M. van Ravenswaaij-Arts, Markus J. van Roosmalen, Sarah Vergult, Catharina M. L. Volker-Touw, Dorothy P. Warburton, Matthew J. Waterman, Susan Wiley, Anna Wilson, Maria de la Concepcion A. Yerena-de Vega, Roberto T. Zori, Brynn Levy, Han G. Brunner, Nicole de Leeuw, Wigard P. Kloosterman, Erik C. Thorland, Cynthia C. Morton, James F. Gusella, Michael E. Talkowski^*

^*Corresponding author for this work

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

165 Citations (Web of Science)

Abstract

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21 % of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADS) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

Original language	English
Pages (from-to)	36-45
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3720
Publication status	Published - Jan 2017

Keywords

AUTISM SPECTRUM DISORDER
DE-NOVO MUTATIONS
SEVERE MENTAL-RETARDATION
OF-FUNCTION MUTATIONS
MICRODELETION SYNDROME
CHROMOSOME REARRANGEMENTS
INTELLECTUAL DISABILITY
STRUCTURAL VARIATION
DEVELOPMENTAL DELAY
CANCER GENOMES

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10.1038/ng.3720

Cite this

Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., Pillalamarri, V., Seabra, C. M., Abbott, M-A., Abdul-Rahman, O. A., Aberg, E., Adley, R., Alcaraz-Estrada, S. L., Alkuraya, F. S., An, Y., Anderson, M-A., Antolik, C., Anyane-Yeboa, K., ... Talkowski, M. E. (2017). The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Nature Genetics, 49(1), 36-45. https://doi.org/10.1038/ng.3720

@article{dd6af23c0edb470db35ab3020dd48796,

title = "The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies",

abstract = "Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21 % of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADS) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.",

keywords = "AUTISM SPECTRUM DISORDER, DE-NOVO MUTATIONS, SEVERE MENTAL-RETARDATION, OF-FUNCTION MUTATIONS, MICRODELETION SYNDROME, CHROMOSOME REARRANGEMENTS, INTELLECTUAL DISABILITY, STRUCTURAL VARIATION, DEVELOPMENTAL DELAY, CANCER GENOMES",

author = "Claire Redin and Harrison Brand and Collins, {Ryan L.} and Tammy Kammin and Elyse Mitchell and Hodge, {Jennelle C.} and Carrie Hanscom and Vamsee Pillalamarri and Seabra, {Catarina M.} and Mary-Alice Abbott and Abdul-Rahman, {Omar A.} and Erika Aberg and Rhett Adley and Alcaraz-Estrada, {Sofia L.} and Alkuraya, {Fowzan S.} and Yu An and Mary-Anne Anderson and Caroline Antolik and Kwame Anyane-Yeboa and Atkin, {Joan F.} and Tina Bartell and Bernstein, {Jonathan A.} and Elizabeth Beyer and Ian Blumenthal and Bongers, {Ernie M. H. F.} and Brilstra, {Eva H.} and Brown, {Chester W.} and Bruggenwirth, {Hennie T.} and Bert Callewaert and Colby Chiang and Ken Corning and Helen Cox and Edwin Cuppen and Currall, {Benjamin B.} and Tom Cushing and Dezso David and Deardorff, {Matthew A.} and Annelies Dheedene and Marc D'Hooghe and {de Vries}, {Bert B. A.} and Earl, {Dawn L.} and Ferguson, {Heather L.} and Heather Fisher and FitzPatrick, {David R.} and Pamela Gerrol and Daniela Giachino and Glessner, {Joseph T.} and Troy Gliem and Margo Grady and Graham, {Brett H.} and Cristin Griffis and Gripp, {Karen W.} and Gropman, {Andrea L.} and Andrea Hanson-Kahn and Harris, {David J.} and Hayden, {Mark A.} and Rosamund Hill and Ron Hochstenbach and Hoffman, {Jodi D.} and Hopkin, {Robert J.} and Hubshman, {Monika W.} and Innes, {A. Micheil} and Mira Irons and Melita Irving and Jacobsen, {Jessie C.} and Sandra Janssens and Tamison Jewett and Johnson, {John P.} and Jongmans, {Marjolijn C.} and Kahler, {Stephen G.} and Koolen, {David A.} and Jerome Korzelius and Kroisel, {Peter M.} and Yves Lacassie and William Lawless and Emmanuelle Lemyre and Kathleen Leppig and Levin, {Alex V.} and Haibo Li and Hong Li and Liao, {Eric C.} and Cynthia Lim and Lose, {Edward J.} and Diane Lucente and Macera, {Michael J.} and Poornima Manavalan and Giorgia Mandrile and Marcelis, {Carlo L.} and Lauren Margolin and Tamara Mason and Diane Masser-Frye and McClellan, {Michael W.} and Mendoza, {Cinthya J. Zepeda} and Bjorn Menten and Sjors Middelkamp and Mikami, {Liya R.} and Emily Moe and Shehla Mohammed and Tarja Mononen and Mortenson, {Megan E.} and Graciela Moya and Nieuwint, {Aggie W.} and Zehra Ordulu and Sandhya Parkash and Pauker, {Susan P.} and Shahrin Pereira and Danielle Perrin and Katy Phelan and {Pina Aguilar}, {Raul E.} and Poddighe, {Pino J.} and Giulia Pregno and Salmo Raskin and Linda Reis and William Rhead and Debra Rita and Ivo Renkens and Filip Roelens and Jayla Ruliera and Patrick Rump and Schilit, {Samantha L. P.} and Ranad Shaheen and Rebecca Sparkes and Erica Spiegel and Blair Stevens and Stone, {Matthew R.} and Julia Tagoe and Thakuria, {Joseph V.} and {van Bon}, {Bregje W.} and {van de Kamp}, Jiddeke and {van Der Burgt}, Ineke and {van Essen}, Ton and {van Ravenswaaij-Arts}, {Conny M.} and {van Roosmalen}, {Markus J.} and Sarah Vergult and Volker-Touw, {Catharina M. L.} and Warburton, {Dorothy P.} and Waterman, {Matthew J.} and Susan Wiley and Anna Wilson and {Yerena-de Vega}, {Maria de la Concepcion A.} and Zori, {Roberto T.} and Brynn Levy and Brunner, {Han G.} and {de Leeuw}, Nicole and Kloosterman, {Wigard P.} and Thorland, {Erik C.} and Morton, {Cynthia C.} and Gusella, {James F.} and Talkowski, {Michael E.}",

year = "2017",

month = jan,

doi = "10.1038/ng.3720",

language = "English",

volume = "49",

pages = "36--45",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

Redin, C, Brand, H, Collins, RL, Kammin, T, Mitchell, E, Hodge, JC, Hanscom, C, Pillalamarri, V, Seabra, CM, Abbott, M-A, Abdul-Rahman, OA, Aberg, E, Adley, R, Alcaraz-Estrada, SL, Alkuraya, FS, An, Y, Anderson, M-A, Antolik, C, Anyane-Yeboa, K, Atkin, JF, Bartell, T, Bernstein, JA, Beyer, E, Blumenthal, I, Bongers, EMHF, Brilstra, EH, Brown, CW, Bruggenwirth, HT, Callewaert, B, Chiang, C, Corning, K, Cox, H, Cuppen, E, Currall, BB, Cushing, T, David, D, Deardorff, MA, Dheedene, A, D'Hooghe, M, de Vries, BBA, Earl, DL, Ferguson, HL, Fisher, H, FitzPatrick, DR, Gerrol, P, Giachino, D, Glessner, JT, Gliem, T, Grady, M, Graham, BH, Griffis, C, Gripp, KW, Gropman, AL, Hanson-Kahn, A, Harris, DJ, Hayden, MA, Hill, R, Hochstenbach, R, Hoffman, JD, Hopkin, RJ, Hubshman, MW, Innes, AM, Irons, M, Irving, M, Jacobsen, JC, Janssens, S, Jewett, T, Johnson, JP, Jongmans, MC, Kahler, SG, Koolen, DA, Korzelius, J, Kroisel, PM, Lacassie, Y, Lawless, W, Lemyre, E, Leppig, K, Levin, AV, Li, H, Li, H, Liao, EC, Lim, C, Lose, EJ, Lucente, D, Macera, MJ, Manavalan, P, Mandrile, G, Marcelis, CL, Margolin, L, Mason, T, Masser-Frye, D, McClellan, MW, Mendoza, CJZ, Menten, B, Middelkamp, S, Mikami, LR, Moe, E, Mohammed, S, Mononen, T, Mortenson, ME, Moya, G, Nieuwint, AW, Ordulu, Z, Parkash, S, Pauker, SP, Pereira, S, Perrin, D, Phelan, K, Pina Aguilar, RE, Poddighe, PJ, Pregno, G, Raskin, S, Reis, L, Rhead, W, Rita, D, Renkens, I, Roelens, F, Ruliera, J, Rump, P, Schilit, SLP, Shaheen, R, Sparkes, R, Spiegel, E, Stevens, B, Stone, MR, Tagoe, J, Thakuria, JV, van Bon, BW, van de Kamp, J, van Der Burgt, I, van Essen, T, van Ravenswaaij-Arts, CM, van Roosmalen, MJ, Vergult, S, Volker-Touw, CML, Warburton, DP, Waterman, MJ, Wiley, S, Wilson, A, Yerena-de Vega, MDLCA, Zori, RT, Levy, B, Brunner, HG, de Leeuw, N, Kloosterman, WP, Thorland, EC, Morton, CC, Gusella, JF & Talkowski, ME 2017, 'The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies', Nature Genetics, vol. 49, no. 1, pp. 36-45. https://doi.org/10.1038/ng.3720

TY - JOUR

T1 - The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

AU - Redin, Claire

AU - Brand, Harrison

AU - Collins, Ryan L.

AU - Kammin, Tammy

AU - Mitchell, Elyse

AU - Hodge, Jennelle C.

AU - Hanscom, Carrie

AU - Pillalamarri, Vamsee

AU - Seabra, Catarina M.

AU - Abbott, Mary-Alice

AU - Abdul-Rahman, Omar A.

AU - Aberg, Erika

AU - Adley, Rhett

AU - Alcaraz-Estrada, Sofia L.

AU - Alkuraya, Fowzan S.

AU - An, Yu

AU - Anderson, Mary-Anne

AU - Antolik, Caroline

AU - Anyane-Yeboa, Kwame

AU - Atkin, Joan F.

AU - Bartell, Tina

AU - Bernstein, Jonathan A.

AU - Beyer, Elizabeth

AU - Blumenthal, Ian

AU - Bongers, Ernie M. H. F.

AU - Brilstra, Eva H.

AU - Brown, Chester W.

AU - Bruggenwirth, Hennie T.

AU - Callewaert, Bert

AU - Chiang, Colby

AU - Corning, Ken

AU - Cox, Helen

AU - Cuppen, Edwin

AU - Currall, Benjamin B.

AU - Cushing, Tom

AU - David, Dezso

AU - Deardorff, Matthew A.

AU - Dheedene, Annelies

AU - D'Hooghe, Marc

AU - de Vries, Bert B. A.

AU - Earl, Dawn L.

AU - Ferguson, Heather L.

AU - Fisher, Heather

AU - FitzPatrick, David R.

AU - Gerrol, Pamela

AU - Giachino, Daniela

AU - Glessner, Joseph T.

AU - Gliem, Troy

AU - Grady, Margo

AU - Graham, Brett H.

AU - Griffis, Cristin

AU - Gripp, Karen W.

AU - Gropman, Andrea L.

AU - Hanson-Kahn, Andrea

AU - Harris, David J.

AU - Hayden, Mark A.

AU - Hill, Rosamund

AU - Hochstenbach, Ron

AU - Hoffman, Jodi D.

AU - Hopkin, Robert J.

AU - Hubshman, Monika W.

AU - Innes, A. Micheil

AU - Irons, Mira

AU - Irving, Melita

AU - Jacobsen, Jessie C.

AU - Janssens, Sandra

AU - Jewett, Tamison

AU - Johnson, John P.

AU - Jongmans, Marjolijn C.

AU - Kahler, Stephen G.

AU - Koolen, David A.

AU - Korzelius, Jerome

AU - Kroisel, Peter M.

AU - Lacassie, Yves

AU - Lawless, William

AU - Lemyre, Emmanuelle

AU - Leppig, Kathleen

AU - Levin, Alex V.

AU - Li, Haibo

AU - Li, Hong

AU - Liao, Eric C.

AU - Lim, Cynthia

AU - Lose, Edward J.

AU - Lucente, Diane

AU - Macera, Michael J.

AU - Manavalan, Poornima

AU - Mandrile, Giorgia

AU - Marcelis, Carlo L.

AU - Margolin, Lauren

AU - Mason, Tamara

AU - Masser-Frye, Diane

AU - McClellan, Michael W.

AU - Mendoza, Cinthya J. Zepeda

AU - Menten, Bjorn

AU - Middelkamp, Sjors

AU - Mikami, Liya R.

AU - Moe, Emily

AU - Mohammed, Shehla

AU - Mononen, Tarja

AU - Mortenson, Megan E.

AU - Moya, Graciela

AU - Nieuwint, Aggie W.

AU - Ordulu, Zehra

AU - Parkash, Sandhya

AU - Pauker, Susan P.

AU - Pereira, Shahrin

AU - Perrin, Danielle

AU - Phelan, Katy

AU - Pina Aguilar, Raul E.

AU - Poddighe, Pino J.

AU - Pregno, Giulia

AU - Raskin, Salmo

AU - Reis, Linda

AU - Rhead, William

AU - Rita, Debra

AU - Renkens, Ivo

AU - Roelens, Filip

AU - Ruliera, Jayla

AU - Rump, Patrick

AU - Schilit, Samantha L. P.

AU - Shaheen, Ranad

AU - Sparkes, Rebecca

AU - Spiegel, Erica

AU - Stevens, Blair

AU - Stone, Matthew R.

AU - Tagoe, Julia

AU - Thakuria, Joseph V.

AU - van Bon, Bregje W.

AU - van de Kamp, Jiddeke

AU - van Der Burgt, Ineke

AU - van Essen, Ton

AU - van Ravenswaaij-Arts, Conny M.

AU - van Roosmalen, Markus J.

AU - Vergult, Sarah

AU - Volker-Touw, Catharina M. L.

AU - Warburton, Dorothy P.

AU - Waterman, Matthew J.

AU - Wiley, Susan

AU - Wilson, Anna

AU - Yerena-de Vega, Maria de la Concepcion A.

AU - Zori, Roberto T.

AU - Levy, Brynn

AU - Brunner, Han G.

AU - de Leeuw, Nicole

AU - Kloosterman, Wigard P.

AU - Thorland, Erik C.

AU - Morton, Cynthia C.

AU - Gusella, James F.

AU - Talkowski, Michael E.

PY - 2017/1

Y1 - 2017/1

N2 - Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21 % of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADS) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

AB - Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21 % of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADS) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

KW - AUTISM SPECTRUM DISORDER

KW - DE-NOVO MUTATIONS

KW - SEVERE MENTAL-RETARDATION

KW - OF-FUNCTION MUTATIONS

KW - MICRODELETION SYNDROME

KW - CHROMOSOME REARRANGEMENTS

KW - INTELLECTUAL DISABILITY

KW - STRUCTURAL VARIATION

KW - DEVELOPMENTAL DELAY

KW - CANCER GENOMES

U2 - 10.1038/ng.3720

DO - 10.1038/ng.3720

M3 - Article

C2 - 27841880

SN - 1061-4036

VL - 49

SP - 36

EP - 45

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -