De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies.
De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies.
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DOI：
10.1002/ajmg.a.38207
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Martinez-Agosto JA
中科院分区：
文献类型：
--
作者：
Mullegama SV;Klein SD;Mulatinho MV;Senaratne TN;Singh K;UCLA Clinical Genomics Center;Nguyen DC;Gallant NM;Strom SP;Ghahremani S;Rao NP;Martinez-Agosto JA
内聚蛋白复合物是一种进化上保守的多亚基蛋白复合物，在有丝分裂和减数分裂过程中调节姐妹染色单体内聚。此外，内聚蛋白复合物调节DNA复制、DNA修复和转录。综合体的核心由四个亚单元组成；SMC1A, SMC3, RAD21, STAG1/2。许多这些蛋白质的功能丧失突变与人类发育障碍有关，统称为“内聚病”。通过对一名8岁女孩的临床外显子组测序，该女孩具有整体发育迟缓、小头畸形、听力损失、语言迟缓、ADHD和畸形特征的临床病史，我们描述了整体黏合结构蛋白STAG2的杂合从头变异（c.205C>T; p.(Arg69*)）。这种变异与STAG2蛋白表达降低有关。此外，中期扩散分析没有显示姊妹染色单体过早分离；然而，观察到姐妹染色单体内聚延迟。为了进一步支持STAG2变异的致病性，我们从破译研究数据库中确定了另外两例女性病例，其STAG2突变和表型与我们的患者相似。有趣的是，这三个病例的临床特征与其他已证实的黏结性疾病非常相似。在此，我们认为STAG2是一种剂量敏感基因，杂合的功能丧失变异会导致粘连病。
The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits; SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed “cohesinopathies”. Through clinical exome sequencing of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. Further, the analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrg3663
发表时间：
2014-04
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Ong CT;Corces VG
通讯作者：
Corces VG
DOI：
10.2147/tacg.s34457
发表时间：
2013
期刊：
The application of clinical genetics
影响因子：
--
作者：
Barbero JL
通讯作者：
Barbero JL
SMC1b存在于哺乳动物体细胞中，并与有丝分裂粘着蛋白相互作用。
影响因子：
4.6
作者：
Mannini L;Cucco F;Quarantotti V;Amato C;Tinti M;Tana L;Frattini A;Delia D;Krantz ID;Jessberger R;Musio A
通讯作者：
Musio A
影响因子：
4.5
作者：
Skibbens RV;Colquhoun JM;Green MJ;Molnar CA;Sin DN;Sullivan BJ;Tanzosh EE
通讯作者：
Tanzosh EE