STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability
STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability
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DOI：
10.1136/jmedgenet-2016-104468
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发表时间：
2017-07-01
影响因子：
4
通讯作者：
Faivre, Laurence
中科院分区：
文献类型：
--
作者：
Lehalle, Daphne;Mosca-Boidron, Anne-Laure;Faivre, Laurence
背景粘连蛋白病是一种罕见的神经发育障碍，由粘连蛋白通路功能障碍引起，粘连蛋白通路使染色体分离并调节基因转录。迄今为止，已经报道了该途径的八个基因与人类疾病有关。 STAG1 与其他五个亚基一起属于核心粘连蛋白复合物的 STAG 亚基。本工作旨在鉴定STAG1突变的表型。方法在全球范围内遗传科转诊的智力障碍（ID）患者中，按照当地诊断标准进行芯片比较基因组杂交（CGH）、基因组、全外显子组测序或全基因组测序。结果在来自16个家庭的17名个体中发现了STAG1突变，其中男性9例，女性8例，年龄2-33岁。四个人携带包含 STAG1 的小微缺失；来自两个家族的三名个体存在基因内 STAG1 缺失。阵列 CGH 鉴定出 6 个缺失，全外显子组测序鉴定出 1 个缺失。全外显子组测序在 8 名患者中发现了从头杂合的错义或移码 STAG1 变异，一组与 ID 相关的基因在两个个体中发现了错义和移码变异。这17名患者有着共同的面部特征，都是嘴巴宽、眼睛深陷。 4 人患有轻度小头畸形，7 人患有癫痫。 结论 我们报告了一项由来自 16 个家庭的 17 人组成的国际系列研究，这些人表现出综合征性非特异性 ID，可能归因于 STAG1 缺失或点突变。第一个系列报道了 STAG1 突变引起的表型，强调了罕见疾病领域数据共享的重要性。
Background Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations.Methods Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.Results A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.Conclusions We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.