Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
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DOI：
10.1111/cge.12105
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发表时间：
2013-12-01
影响因子：
3.5
通讯作者：
Kutsche, K.
中科院分区：
文献类型：
--
作者：
Chiliana, B.;Abdollahpour, H.;Kutsche, K.
突触病变是一组神经系统疾病，包括自闭症谱系障碍（ASD）和智力残疾（ID）。它们与编码对突触形成和稳定重要的蛋白质的基因突变有关，如SHANK 1 -3。在ASD和ID患者中已发现SHANK基因的功能缺失突变，这表明其他因素改变了神经系统表型。我们报告一个男孩，患有严重的ID，行为异常和语言障碍，携带平衡的从头三重易位46，XY，t（11;17;19）（q13.3;q25.1;q13.42）。发现11q13.3断裂点破坏SHANK 2基因。该患者还携带15q13.3和10q22.11的拷贝数变异，包括ARHGAP 11B和两个突触基因。编码7-烟碱乙酰胆碱受体亚基的CHRNA 7基因和编码G蛋白调节的神经突生长诱导剂2的GPRIN 2基因被复制。在两名患有ASD和ID的患者以及患有t（11;17;19）、严重ID和行为问题的患者中，新发SHANK 2突变和CHRNA 7重复的共同发生表明这些基因在共同的突触通路上会聚。我们的研究结果加强了寡基因遗传模型，并强调了一个大的影响突变和修饰基因共同决定突触病的表型表达的存在。
Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding 7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.