Mullegama Sureni V, Klein Steven D, Mulatinho Milene V, Senaratne Tharanga Niroshini, Singh Kathryn, Nguyen Dzung C, Gallant Natalie M, Strom Samuel P, Ghahremani Shahnaz, Rao Nagesh P, Martinez-Agosto Julian A
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
UCLA Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, California.
Am J Med Genet A. 2017 May;173(5):1319-1327. doi: 10.1002/ajmg.a.38207. Epub 2017 Mar 11.
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 (CES) 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. 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.
黏连蛋白复合体是一种在进化上保守的多亚基蛋白质复合体，在有丝分裂和减数分裂过程中调节姐妹染色单体黏连。此外，黏连蛋白复合体还调节DNA复制、DNA修复和转录。该复合体的核心由四个亚基组成：SMC1A、SMC3、RAD21和STAG1/2。这些蛋白质中许多的功能丧失突变与统称为“黏连蛋白病”的人类发育障碍有关。通过对一名有全球发育迟缓、小头畸形、伴有听力损失的小耳畸形、语言发育迟缓、注意力缺陷多动障碍和畸形特征临床病史的8岁女孩进行临床外显子组测序（CES），我们描述了整合黏连蛋白结构蛋白STAG2中的一个杂合新生变体（c.205C>T；p.(Arg69*)）。该变体与STAG2蛋白表达降低有关。中期染色体铺展分析未显示姐妹染色单体过早分离；然而，观察到姐妹染色单体黏连延迟。为了进一步支持STAG2变体的致病性，我们从DECIPHER研究数据库中鉴定出另外两名女性病例，她们的STAG2存在突变，且表型与我们的患者相似。有趣的是，这三例病例的临床特征与其他已明确的黏连蛋白病中观察到的特征非常相似。在此，我们认为STAG2是一个剂量敏感基因，杂合功能丧失变体导致黏连蛋白病。
