Title

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

Authors

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 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

Document Type

Article

Publication Date

1-1-2017

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.

Publisher

Nature Pub. Co.

Publication Title

Nature genetics

ISSN

1546-1718

Volume

49

Issue

1

First Page

36

Last Page

45

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