自闭症谱系障碍(ASD)通常伴有智力障碍(ID)。尽管进行了广泛的研究,然而,这种共病的遗传基础仍然不清楚。在这项研究中,我们试图开发一个分析ASD中从头突变和与ID表型相关的可能通路的流程.进行全外显子组测序(WES)以筛选79名ASD儿童及其父母(三重奏)中的从头突变和候选基因。分析了与ID表型相关的从头改变基因和相关途径。选择上述途径的连接节点(基因),并评估了这些选定基因在研究人群中对ID表型的诊断价值。
我们鉴定出89个从头突变基因,其中34个基因先前报道与ASD有关,包括NOTCH1基因EGF重复序列中的双重命中(p。V999M和p.S1027L)。有趣的是,在这34个基因中,22可能直接影响智商(IQ)。进一步的分析表明,这些智商相关的基因富含蛋白质合成,能量代谢,和氨基酸代谢,和至少9个基因(CACNA1A,ALG9,PALM2,MGAT4A,PCK2,PLEKHA1,PSME3,ADI1和TLE3)参与了所有这三种途径。7名携带这些基因突变的患者表现出低智商评分的高患病率(<70),一种非语言,和早期诊断年龄(<4岁)。此外,我们的这9个基因小组在智商评分低的早期诊断患者中的诊断率达到了10.2%(5/49),在智商评分低和非语言的患者中的诊断率也达到了10%(4/40).
在这项研究中,我们发现了一些伴随智力障碍的ASD的新遗传倾向。我们的结果可能有助于ASD的病因研究和智力障碍的早期诊断。有必要进行更大规模的人群研究和进一步的机制研究。
Autism spectrum disorder (ASD) is often accompanied by intellectual disability (ID). Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we tried to develop an analyzing pipeline for de novo mutations and possible pathways related to ID phenotype in ASD. Whole-exome sequencing (WES) was performed to screen de novo mutations and candidate genes in 79 ASD children together with their parents (trios). The de novo altering genes and relative pathways which were associated with ID phenotype were analyzed. The connection nodes (genes) of above pathways were selected, and the diagnostic value of these selected genes for ID phenotype in the study population was also evaluated.
We identified 89 de novo mutant genes, of which 34 genes were previously reported to be associated with ASD, including double hits in the EGF repeats of NOTCH1 gene (p.V999M and p.S1027L). Interestingly, of these 34 genes, 22 may directly affect intelligence quotient (IQ). Further analyses revealed that these IQ-related genes were enriched in protein synthesis, energy metabolism, and amino acid metabolism, and at least 9 genes (CACNA1A, ALG9, PALM2, MGAT4A, PCK2, PLEKHA1, PSME3, ADI1, and TLE3) were involved in all these three pathways. Seven patients who harbored these gene mutations showed a high prevalence of a low IQ score (< 70), a non-verbal language, and an early diagnostic age (< 4 years). Furthermore, our panel of these 9 genes reached a 10.2% diagnostic rate (5/49) in early diagnostic patients with a low IQ score and also reached a 10% diagnostic yield in those with both a low IQ score and non-verbal language (4/40).
We found some new genetic disposition for ASD accompanied with intellectual disability in this study. Our results may be helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted.