Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders
Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders
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DOI：
10.1038/ejhg.2012.175
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Schwartz, Charles E.
中科院分区：
文献类型：
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作者：
Boccuto, Luigi;Lauri, Maria;Schwartz, Charles E.
自闭症谱系障碍（ASD）包括三种主要病症：自闭症障碍（AD）、未另作说明的广泛性发育障碍（PDD-NOS）和普氏综合征。已经表明，许多与ASD相关的基因参与谷氨酸突触处的神经胶质素-神经节素相互作用：NLGN 3、NLGN 4、NRXN 1、CNTNAP 2和SHANK 3。我们在两组ASD患者（133例来自美国，88例来自意大利）中筛选了最后一个基因。我们发现5/221例（2.3%）病例有致病性改变：一个106 kb的SHANK 3基因缺失，两个导致提前终止密码子的移码突变，一个错义突变（p.Pro141AIa）和一个剪接突变（c.1820-4G>A）。此外，在17名患者（7.7%）中，我们检测到c.1304+ 48 C>T转换影响CpG岛中的甲基化胞嘧啶。该变体被报告为SNP rs76224556，并且在美国和意大利对照组中均发现，但在我们的病例中其结果比对照组显著更频繁。该变体在PDD-NOS病例中也比在AD病例中更常见。我们还在104名美国ASD患者的独立复制队列中筛选了该基因，其中我们在1名患者（0.9%）中发现错义突变（p.AIa1468Ser），在8名患者（7.7%）中检测到c.1304+ 48 C>T转换。虽然SHANK 3变体存在于任何ASD亚型中，但SNP rs76224556似乎与PDD-NOS病例显着相关。这代表了自闭症谱系障碍基因型与表型相关性的第一个证据，并强调了详细的临床神经精神评估对于自闭症谱系障碍患者有效基因筛查的重要性。European Journal of Human Genetics（2013）21，310-316; doi：10.1038/ejhg.2012.175; 2012年8月15日在线发表
Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141AIa), and a splicing mutation (c.1820-4G>A). Additionally, in 17 patients (7.7%) we detected a c.1304+48C>T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.AIa1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304+48C>T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients. European Journal of Human Genetics (2013) 21, 310-316; doi:10.1038/ejhg.2012.175; published online 15 August 2012