Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.
Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.
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DOI：
10.1136/jmedgenet-2014-102573
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发表时间：
2014-10
影响因子：
4
通讯作者：
FitzPatrick DR
中科院分区：
文献类型：
--
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
科尔内利亚德兰格综合征（CdLS）是一种以面部特征、智力障碍和生长迟缓为主要特征的多系统疾病。大多数具有典型CdLS的个体在NIPBL中具有新生杂合功能丧失突变，其中镶嵌个体占显著比例。其他粘附素组分SMC 1A、SMC 3、HDAC 8和RAD 21中的突变引起不太典型的CdLS。我们筛选了163名已知基因编码区突变的受影响个体，90名基因组重排，19名NIPBL深层内含子变异，5名进行了全外显子组测序。致病性突变[包括镶嵌变化]在以下中被鉴定：NIPBL 46 [3]（28.2%）; SMC 1A 5 [1]（3.1%）; SMC 3 5 [1]（3.1%）; HDAC 8 6 [0]（3.6%）和RAD 21 1 [0]（0.6%）。1例患者的1p36.3出现了1.3 Mb的从头缺失。另一个有一个520 kb的12q13.13重复，包含ESPL 1，编码分离酶，一种切割粘蛋白环的酶。 在ANKRD 11中鉴定了三个新发突变，证明与KBG综合征的表型重叠。为了估计未检测到的马赛克案件的数量，我们使用递归分区，以确定区分功能的NIPBL阳性亚组。对这些特征的突变阴性组的过滤将至少18%分类为“NIPBL样”。这类NIPBL亚组的平均脸的计算机组成在外观上也比突变阴性组中的所有其他亚组更典型，支持存在未检测到的镶嵌病例。因此，未来在“突变阴性”CdLS中的诊断测试需要对来自不同组织的多个DNA样本进行更深入的测序。
Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
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影响因子：
--
作者：
Gervasini C;Picinelli C;Azzollini J;Rusconi D;Masciadri M;Cereda A;Marzocchi C;Zampino G;Selicorni A;Tenconi R;Russo S;Larizza L;Finelli P
通讯作者：
Finelli P
影响因子：
0.7
作者：
Murray, Jennie E.;Walayat, Muhammed;FitzPatrick, David R.
通讯作者：
FitzPatrick, David R.
影响因子：
2
作者：
Pie, Juan;Concepcion Gil-Rodriguez, Maria;Ciero, Milagros;Lopez-Vinas, Eduardo;Pilar Ribate, Maria;Arnedo, Maria;Deardorff, Matthew A.;Puisac, Beatriz;Legarreta, Jesus;Carlos de Karam, Juan;Rubio, Encarnacion;Bueno, Ines;Baldellou, Antonio;Teresa Calvo, Ma;Casals, Nuria;Luis Olivares, Jose;Losada, Ana;Hegardt, Fausto G.;Krantz, Ian D.;Gomez-Puertas, Paulino;Ramos, Feliciano J.
通讯作者：
Ramos, Feliciano J.
影响因子：
64.5
作者：
Ciosk, R;Zachariae, W;Nasmyth, K
通讯作者：
Nasmyth, K
DOI：
10.1016/s0360-3016(96)00619-0
发表时间：
1997-03-01
影响因子：
7
作者：
Gaspar, L;Scott, C;Byhardt, R
通讯作者：
Byhardt, R