Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability
Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability
复制标题
DOI：
10.1126/scitranslmed.3001267
复制
发表时间：
2010-09-15
影响因子：
17.1
通讯作者：
Vincent, John B.
中科院分区：
文献类型：
--
作者：
Noor, Abdul;Whibley, Annabel;Vincent, John B.
自闭症是一种常见的神经发育障碍，具有复杂的遗传模式。它是遗传性最强的复杂疾病之一，尽管潜在的遗传因素在很大程度上仍不清楚。在这里，我们报告了七个自闭症谱系障碍(ASD)家系和三个智力残疾家系中X染色体PTCHD1(补丁相关)基因的突变。在两个兄弟中发现了跨越外显子1的167千碱基的微缺失，其中一个患有自闭症，另一个患有学习障碍和自闭症特征；在第二个家族中的三名男性智障患者中发现了跨越整个基因的90千碱基的微缺失。在900名患有自闭症的先证者和208名智力残疾的男性先证者中，我们发现了7种不同的错义改变(在8名男性先证者中)，这些错义改变是从未受影响的母亲那里遗传的，在对照组中没有发现。有错义改变的两个ASD个体还携带另一个ASD易感基因(DPYD和DPP6)的从头缺失，这表明复杂的遗传因素。在其他患有ASD的男性中，我们发现了PTCHD1 5‘侧翼区的缺失，该缺失扰乱了一个复杂的非编码RNA和潜在的调节元件；在男性对照组中没有发现类似的变化。因此，我们对PTCHD1及其5‘侧翼区域的系统筛查表明，该基因座与大约1%的自闭症和智力残疾患者有关。
Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex non-coding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in similar to 1% of individuals with ASD and intellectual disability.