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. 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 E. Piña 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 journalArticleAcademicpeer-review

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
DOIs
Publication statusPublished - 1 Jan 2017

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