The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
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DOI：
10.1038/ng.3720
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发表时间：
2017-01
期刊：
影响因子：
30.8
通讯作者：
Talkowski ME
中科院分区：
文献类型：
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作者：
Redin C;Brand H;Collins RL;Kammin T;Mitchell E;Hodge JC;Hanscom C;Pillalamarri V;Seabra CM;Abbott MA;Abdul-Rahman OA;Aberg E;Adley R;Alcaraz-Estrada SL;Alkuraya FS;An Y;Anderson MA;Antolik C;Anyane-Yeboa K;Atkin JF;Bartell T;Bernstein JA;Beyer E;Blumenthal I;Bongers EM;Brilstra EH;Brown CW;Brüggenwirth HT;Callewaert B;Chiang C;Corning K;Cox H;Cuppen E;Currall BB;Cushing T;David D;Deardorff MA;Dheedene A;D'Hooghe M;de Vries BB;Earl DL;Ferguson HL;Fisher H;FitzPatrick DR;Gerrol P;Giachino D;Glessner JT;Gliem T;Grady M;Graham BH;Griffis C;Gripp KW;Gropman AL;Hanson-Kahn A;Harris DJ;Hayden MA;Hill R;Hochstenbach R;Hoffman JD;Hopkin RJ;Hubshman MW;Innes AM;Irons M;Irving M;Jacobsen JC;Janssens S;Jewett T;Johnson JP;Jongmans MC;Kahler SG;Koolen DA;Korzelius J;Kroisel PM;Lacassie Y;Lawless W;Lemyre E;Leppig K;Levin AV;Li H;Li H;Liao EC;Lim C;Lose EJ;Lucente D;Macera MJ;Manavalan P;Mandrile G;Marcelis CL;Margolin L;Mason T;Masser-Frye D;McClellan MW;Mendoza CJ;Menten B;Middelkamp S;Mikami LR;Moe E;Mohammed S;Mononen T;Mortenson ME;Moya G;Nieuwint AW;Ordulu Z;Parkash S;Pauker SP;Pereira S;Perrin D;Phelan K;Aguilar RE;Poddighe PJ;Pregno G;Raskin S;Reis L;Rhead W;Rita D;Renkens I;Roelens F;Ruliera J;Rump P;Schilit SL;Shaheen R;Sparkes R;Spiegel E;Stevens B;Stone MR;Tagoe J;Thakuria JV;van Bon BW;van de Kamp J;van Der Burgt I;van Essen T;van Ravenswaaij-Arts CM;van Roosmalen MJ;Vergult S;Volker-Touw CM;Warburton DP;Waterman MJ;Wiley S;Wilson A;Yerena-de Vega MC;Zori RT;Levy B;Brunner HG;de Leeuw N;Kloosterman WP;Thorland EC;Morton CC;Gusella JF;Talkowski ME
尽管其临床意义，平衡染色体异常（BCA）的表征在很大程度上被限制到细胞遗传学分辨率。我们在273例有一系列先天性异常的受试者中，以核苷酸分辨率探索了BCA的景观。全基因组测序修改了93%的核型，并揭示了21%的BCA核型分析的复杂性，突出了传统细胞遗传学方法的局限性。至少33.9%的BCA导致基因破坏，可能有助于发育表型，5.2%与致病性基因组失衡，7.3%破坏拓扑相关域（TADs），包括已知的综合征位点。值得注意的是，8名受试者的BCA断点改变了一个包含MEF2C的单一序列，MEF2C是5q14.3微缺失综合征的已知驱动因素，导致MEF2C表达降低。这项研究提出，序列水平的分辨率显着提高了平衡重排的临床结果的预测，并提供了新的致病机制，如由于染色体拓扑结构的变化而改变的调节洞察。
Despite their clinical significance, characterization of balanced chromosomal abnormalities (BCAs) 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 revealed 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. This study proposes that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements, and provides insight into novel pathogenic mechanisms such as altered regulation due to changes in chromosome topology.