The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
Claire RedinHarrison BrandRyan L CollinsTammy KamminElyse MitchellJennelle C HodgeCarrie HanscomVamsee PillalamarriCatarina M SeabraMary-Alice AbbottOmar A Abdul-RahmanErika AbergRhett AdleySofia L Alcaraz-EstradaFowzan Sami AlkurayaYu AnMary-Anne AndersonCaroline AntolikKwame Anyane-YeboaJoan F AtkinTina BartellJonathan A BernsteinElizabeth BeyerIan BlumenthalErnie M H F BongersEva H BrilstraChester W BrownHennie T BrüggenwirthBert CallewaertColby ChiangKen CorningHelen CoxEdwin CuppenBenjamin B CurrallTom CushingDezso DavidMatthew A DeardorffAnnelies DheedeneMarc D'HoogheBert B A de VriesDawn L EarlHeather L FergusonHeather FisherDavid R FitzPatrickPamela GerrolDaniela GiachinoJoseph T GlessnerTroy GliemMargo GradyBrett H GrahamCristin GriffisKaren W GrippAndrea L GropmanAndrea Hanson-KahnDavid J HarrisMark A HaydenRosamund HillRon HochstenbachJodi D HoffmanRobert J HopkinMonika W HubshmanA Micheil InnesMira IronsMelita IrvingJessie C JacobsenSandra JanssensTamison JewettJohn P JohnsonMarjolijn C JongmansStephen G KahlerDavid A KoolenJerome KorzeliusPeter M KroiselYves LacassieWilliam LawlessEmmanuelle LemyreKathleen LeppigAlex V LevinHaibo LiHong LiEric C LiaoCynthia LimEdward J LoseDiane LucenteMichael J MaceraPoornima ManavalanGiorgia MandrileCarlo L MarcelisLauren MargolinTamara MasonDiane Masser-FryeMichael W McClellanCinthya J Zepeda MendozaBjörn MentenSjors MiddelkampLiya R MikamiEmily MoeShehla MohammedTarja MononenMegan E MortensonGraciela MoyaAggie W NieuwintZehra OrduluSandhya ParkashSusan P PaukerShahrin PereiraDanielle PerrinKaty PhelanRaul E Piña AguilarPino J PoddigheGiulia PregnoSalmo RaskinLinda ReisWilliam RheadDebra RitaIvo RenkensFilip RoelensJayla RulieraPatrick RumpSamantha L P SchilitRanad ShaheenRebecca SparkesErica SpiegelBlair StevensMatthew R StoneJulia TagoeJoseph V ThakuriaBregje W van BonJiddeke van de KampIneke van Der BurgtTon van EssenConny M van Ravenswaaij-ArtsMarkus J van RoosmalenSarah VergultCatharina M L Volker-TouwDorothy P WarburtonMatthew J WatermanSusan WileyAnna WilsonMaria de la Concepcion A Yerena-de VegaRoberto T ZoriBrynn LevyHan G BrunnerNicole de LeeuwWigard P KloostermanErik C ThorlandCynthia C MortonJames F GusellaMichael E TalkowskiPublished in: Nature genetics (2016)
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.