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 & 129 others Tina Bartell, Jonathan A Bernstein, Elizabeth Beyer, Ian Blumenthal, Ernie M H F Bongers, Eva H Brilstra, Chester W Brown, Hennie T Brüggenwirth, 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, Björn 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 Eduardo 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

Research output: Contribution to journalArticle

65 Citations (Scopus)
6 Downloads (Pure)

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 languageEnglish
Pages (from-to)36-45
Number of pages10
JournalNature Genetics
Volume49
Issue number1
Early online date14 Nov 2016
DOIs
Publication statusPublished - Jan 2017

Fingerprint

Chromosome Aberrations
Cytogenetics
Karyotyping
Karyotype
Nucleotides
Chromosomes
Genome
Phenotype
Genes

Keywords

  • cytogenetics
  • structural variation
  • balanced chromosomal abnormality
  • congenital anomaly
  • intellectual disability
  • autism
  • translocation
  • inversion
  • chromothripsis
  • topologically associated domain (TAD)
  • MEF2C

Cite this

Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., ... 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

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

In: Nature Genetics, Vol. 49, No. 1, 01.2017, p. 36-45.

Research output: Contribution to journalArticle

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, Brüggenwirth, 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
Redin, Claire ; Brand, Harrison ; Collins, Ryan L ; Kammin, Tammy ; Mitchell, Elyse ; Hodge, Jennelle C ; Hanscom, Carrie ; Pillalamarri, Vamsee ; Seabra, Catarina M ; Abbott, Mary-Alice ; Abdul-Rahman, Omar A ; Aberg, Erika ; Adley, Rhett ; Alcaraz-Estrada, Sofia L ; Alkuraya, Fowzan S ; An, Yu ; Anderson, Mary-Anne ; Antolik, Caroline ; Anyane-Yeboa, Kwame ; Atkin, Joan F ; Bartell, Tina ; Bernstein, Jonathan A ; Beyer, Elizabeth ; Blumenthal, Ian ; Bongers, Ernie M H F ; Brilstra, Eva H ; Brown, Chester W ; Brüggenwirth, Hennie T ; Callewaert, Bert ; Chiang, Colby ; Corning, Ken ; Cox, Helen ; Cuppen, Edwin ; Currall, Benjamin B ; Cushing, Tom ; David, Dezso ; Deardorff, Matthew A ; Dheedene, Annelies ; D'Hooghe, Marc ; de Vries, Bert B A ; Earl, Dawn L ; Ferguson, Heather L ; Fisher, Heather ; FitzPatrick, David R ; Gerrol, Pamela ; Giachino, Daniela ; Glessner, Joseph T ; Gliem, Troy ; Grady, Margo ; Graham, Brett H ; Griffis, Cristin ; Gripp, Karen W ; Gropman, Andrea L ; Hanson-Kahn, Andrea ; Harris, David J ; Hayden, Mark A ; Hill, Rosamund ; Hochstenbach, Ron ; Hoffman, Jodi D ; Hopkin, Robert J ; Hubshman, Monika W ; Innes, A Micheil ; Irons, Mira ; Irving, Melita ; Jacobsen, Jessie C ; Janssens, Sandra ; Jewett, Tamison ; Johnson, John P ; Jongmans, Marjolijn C ; Kahler, Stephen G ; Koolen, David A ; Korzelius, Jerome ; Kroisel, Peter M ; Lacassie, Yves ; Lawless, William ; Lemyre, Emmanuelle ; Leppig, Kathleen ; Levin, Alex V ; Li, Haibo ; Li, Hong ; Liao, Eric C ; Lim, Cynthia ; Lose, Edward J ; Lucente, Diane ; Macera, Michael J ; Manavalan, Poornima ; Mandrile, Giorgia ; Marcelis, Carlo L ; Margolin, Lauren ; Mason, Tamara ; Masser-Frye, Diane ; McClellan, Michael W ; Mendoza, Cinthya J Zepeda ; Menten, Björn ; Middelkamp, Sjors ; Mikami, Liya R ; Moe, Emily ; Mohammed, Shehla ; Mononen, Tarja ; Mortenson, Megan E ; Moya, Graciela ; Nieuwint, Aggie W ; Ordulu, Zehra ; Parkash, Sandhya ; Pauker, Susan P ; Pereira, Shahrin ; Perrin, Danielle ; Phelan, Katy ; Pina Aguilar, Raul Eduardo ; Poddighe, Pino J ; Pregno, Giulia ; Raskin, Salmo ; Reis, Linda ; Rhead, William ; Rita, Debra ; Renkens, Ivo ; Roelens, Filip ; Ruliera, Jayla ; Rump, Patrick ; Schilit, Samantha L P ; Shaheen, Ranad ; Sparkes, Rebecca ; Spiegel, Erica ; Stevens, Blair ; Stone, Matthew R ; Tagoe, Julia ; Thakuria, Joseph V ; van Bon, Bregje W ; van de Kamp, Jiddeke ; van Der Burgt, Ineke ; van Essen, Ton ; van Ravenswaaij-Arts, Conny M ; van Roosmalen, Markus J ; Vergult, Sarah ; Volker-Touw, Catharina M L ; Warburton, Dorothy P ; Waterman, Matthew J ; Wiley, Susan ; Wilson, Anna ; Yerena-de Vega, Maria de la Concepcion A ; Zori, Roberto T ; Levy, Brynn ; Brunner, Han G ; de Leeuw, Nicole ; Kloosterman, Wigard P ; Thorland, Erik C ; Morton, Cynthia C ; Gusella, James F ; Talkowski, Michael E. / The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. In: Nature Genetics. 2017 ; Vol. 49, No. 1. pp. 36-45.
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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.",
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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 - Brüggenwirth, 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, Björn

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 Eduardo

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 - cytogenetics

KW - structural variation

KW - balanced chromosomal abnormality

KW - congenital anomaly

KW - intellectual disability

KW - autism

KW - translocation

KW - inversion

KW - chromothripsis

KW - topologically associated domain (TAD)

KW - MEF2C

U2 - 10.1038/ng.3720

DO - 10.1038/ng.3720

M3 - Article

VL - 49

SP - 36

EP - 45

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -