학술논문

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies
Document Type
Report
Author
Redin, ClaireBrand, HarrisonCollins, Ryan LKammin, TammyMitchell, ElyseHodge, Jennelle CHanscom, CarriePillalamarri, VamseeSeabra, Catarina MAbbott, Mary-AliceAbdul-Rahman, Omar AAberg, ErikaAdley, RhettAlcaraz-Estrada, Sofia LAlkuraya, Fowzan SAn, YuAnderson, Mary-AnneAntolik, CarolineAnyane-Yeboa, KwameAtkin, Joan FBartell, TinaBernstein, Jonathan ABeyer, ElizabethBlumenthal, IanBongers, Ernie M H FBrilstra, Eva HBrown, Chester WBrüggenwirth, Hennie TCallewaert, BertChiang, ColbyCorning, KenCox, HelenCuppen, EdwinCurrall, Benjamin BCushing, TomDavid, DezsoDeardorff, Matthew ADheedene, AnneliesD'Hooghe, Marcde Vries, Bert B AEarl, Dawn LFerguson, Heather LFisher, HeatherFitzPatrick, David RGerrol, PamelaGiachino, DanielaGlessner, Joseph TGliem, TroyGrady, MargoGraham, Brett HGriffis, CristinGripp, Karen WGropman, Andrea LHanson-Kahn, AndreaHarris, David JHayden, Mark AHill, RosamundHochstenbach, RonHoffman, Jodi DHopkin, Robert JHubshman, Monika WInnes, A MicheilIrons, MiraIrving, MelitaJacobsen, Jessie CJanssens, SandraJewett, TamisonJohnson, John PJongmans, Marjolijn CKahler, Stephen GKoolen, David AKorzelius, JeromeKroisel, Peter MLacassie, YvesLawless, WilliamLemyre, EmmanuelleLeppig, KathleenLevin, Alex VLi, HaiboLi, HongLiao, Eric CLim, CynthiaLose, Edward JLucente, DianeMacera, Michael JManavalan, PoornimaMandrile, GiorgiaMarcelis, Carlo LMargolin, LaurenMason, TamaraMasser-Frye, DianeMcClellan, Michael WMendoza, Cinthya J ZepedaMenten, BjörnMiddelkamp, SjorsMikami, Liya RMoe, EmilyMohammed, ShehlaMononen, TarjaMortenson, Megan EMoya, GracielaNieuwint, Aggie WOrdulu, ZehraParkash, SandhyaPauker, Susan PPereira, ShahrinPerrin, DaniellePhelan, KatyAguilar, Raul E PiñaPoddighe, Pino JPregno, GiuliaRaskin, SalmoReis, LindaRhead, WilliamRita, DebraRenkens, IvoRoelens, FilipRuliera, JaylaRump, PatrickSchilit, Samantha L PShaheen, RanadSparkes, RebeccaSpiegel, EricaStevens, BlairStone, Matthew RTagoe, JuliaThakuria, Joseph Vvan Bon, Bregje Wvan de Kamp, Jiddekevan Der Burgt, Inekevan Essen, Tonvan Ravenswaaij-Arts, Conny Mvan Roosmalen, Markus JVergult, SarahVolker-Touw, Catharina M LWarburton, Dorothy PWaterman, Matthew JWiley, SusanWilson, AnnaYerena-de Vega, Maria de la Concepcion AZori, Roberto TLevy, BrynnBrunner, Han Gde Leeuw, NicoleKloosterman, Wigard PThorland, Erik CMorton, Cynthia CGusella, James FTalkowski, Michael E
Source
Nature Genetics. January 2017, Vol. 49 Issue 1, p36, 10 p.
Subject
Analysis
DNA sequencing -- Analysis
Cytogenetics -- Analysis
Genomics -- Analysis
Language
English
ISSN
1061-4036
Abstract
Author(s): Claire Redin [1, 2, 3]; Harrison Brand [1, 2, 3]; Ryan L Collins [1, 2, 3, 4]; Tammy Kammin [5]; Elyse Mitchell [6]; Jennelle C Hodge [6, 7, 8]; [...]
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.