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 | |
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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In: Nature Genetics, Vol. 49, No. 1, 01.2017, p. 36-45.
Research output: Contribution to journal › Article › Academic › peer-review
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 -