Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.
Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.
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临床外显子组测序揭示了粘粘性的基因座异质性和表型变异性。
DOI：
10.1038/s41436-018-0085-6
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Yuan B;Neira J;Pehlivan D;Santiago-Sim T;Song X;Rosenfeld J;Posey JE;Patel V;Jin W;Adam MP;Baple EL;Dean J;Fong CT;Hickey SE;Hudgins L;Leon E;Madan-Khetarpal S;Rawlins L;Rustad CF;Stray-Pedersen A;Tveten K;Wenger O;Diaz J;Jenkins L;Martin L;McGuire M;Pietryga M;Ramsdell L;Slattery L;DDD Study;Abid F;Bertuch AA;Grange D;Immken L;Schaaf CP;Van Esch H;Bi W;Cheung SW;Breman AM;Smith JL;Shaw C;Crosby AH;Eng C;Yang Y;Lupski JR;Xiao R;Liu P
黏连蛋白途径的缺陷与黏连蛋白病相关，特别是科尔内利亚德兰格综合征（CdLS）。我们的目的是从临床外显子组的角度来描述已知和候选的粘着蛋白病基因的突变。我们回顾性研究了临床外显子组测序（CES，N= 10，698）的患者。在新的或最近描述的cohesinopathy基因的致病变异的患者被招募进行表型表征。致病性或可能致病的单核苷酸和插入/缺失变体（SNV/indel）在已建立的疾病基因中鉴定，包括NIPBL（N=5）、SMC 1A（N=14）、SMC 3（N=4）、RAD 21（N=2）和HDAC 8（N=8）。与表型驱动的队列相比，该遗传定义的队列中的表型偏向CdLS谱的轻度端。候选或最近报道的粘着蛋白病基因由STAG 1（N=3）、STAG 2（N=5）、PDS 5A（N=1）和WAPL（N=1）中的从头SNV/插入缺失以及PDS 5A中的一个遗传SNV支持。我们还确定了影响STAG 1（两个新生，一个未知遗传）和STAG 2（一个未知遗传）的拷贝数缺失。STAG 1和STAG 2变异的患者表现出重叠的特征，但没有CdLS的特征性面部特征。CES有效地鉴定了Cohensinopathy谱轻度端的致病等位基因，并使候选疾病基因的表征成为可能。
Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange Syndrome (CdLS). We aim to delineate mutations in known and candidate cohesinopathy genes from a clinical exome perspective. We retrospectively studied patients referred for clinical exome sequencing (CES, N=10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. Pathogenic or likely pathogenic single nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N=5), SMC1A (N=14), SMC3 (N=4), RAD21 (N=2) and HDAC8 (N=8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared to phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N=3), STAG2 (N=5), PDS5A (N=1) and WAPL (N=1), and one inherited SNV in PDS5A. We also identified copy number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.
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影响因子：
4
作者：
Ansari M;Poke G;Ferry Q;Williamson K;Aldridge R;Meynert AM;Bengani H;Chan CY;Kayserili H;Avci S;Hennekam RC;Lampe AK;Redeker E;Homfray T;Ross A;Falkenberg Smeland M;Mansour S;Parker MJ;Cook JA;Splitt M;Fisher RB;Fryer A;Magee AC;Wilkie A;Barnicoat A;Brady AF;Cooper NS;Mercer C;Deshpande C;Bennett CP;Pilz DT;Ruddy D;Cilliers D;Johnson DS;Josifova D;Rosser E;Thompson EM;Wakeling E;Kinning E;Stewart F;Flinter F;Girisha KM;Cox H;Firth HV;Kingston H;Wee JS;Hurst JA;Clayton-Smith J;Tolmie J;Vogt J;Tatton-Brown K;Chandler K;Prescott K;Wilson L;Behnam M;McEntagart M;Davidson R;Lynch SA;Sisodiya S;Mehta SG;McKee SA;Mohammed S;Holden S;Park SM;Holder SE;Harrison V;McConnell V;Lam WK;Green AJ;Donnai D;Bitner-Glindzicz M;Donnelly DE;Nellåker C;Taylor MS;FitzPatrick DR
通讯作者：
FitzPatrick DR
影响因子：
4
作者：
Lehalle, Daphne;Mosca-Boidron, Anne-Laure;Faivre, Laurence
通讯作者：
Faivre, Laurence
DOI：
10.1056/nejmoa1516767
发表时间：
2017-01-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Posey JE;Harel T;Liu P;Rosenfeld JA;James RA;Coban Akdemir ZH;Walkiewicz M;Bi W;Xiao R;Ding Y;Xia F;Beaudet AL;Muzny DM;Gibbs RA;Boerwinkle E;Eng CM;Sutton VR;Shaw CA;Plon SE;Yang Y;Lupski JR
通讯作者：
Lupski JR
影响因子：
8.8
作者：
Pehlivan, Davut;Hullings, Melanie;Lupski, James R.
通讯作者：
Lupski, James R.
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.