Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.

In addition to cohorts of Parents (N=418), Siblings (N=50), and Probands (N=209), the publication publication describes a subset of male (N=47) and female (N=26) autistic subjects, with significant impairment and intellectual disability, and with cognitive impairment, respectively. These subsets have been defined based on hi/low IQ value in Supplementary Table 1 from the publication.

Publication Abstract:

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected l-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

除包含父母队列（N=418）、兄弟姐妹队列（N=50）以及先证者（Probands）队列（N=209）外，该论文还描述了一组自闭症受试者亚群：其中男性受试者47名（N=47）、女性受试者26名（N=26），分别伴有显著功能损害与智力障碍、认知障碍。上述亚群依据该论文补充表1中的高/低IQ值进行划分。

论文摘要：
目前学界已达成共识，自闭症谱系障碍（ASD）具有显著遗传倾向；然而，至少70%的病例其潜在遗传病因仍未明确。本研究提出假说：在无自闭症谱系障碍或相关表型既往病史的家庭（即所谓散发或单纯型家庭）中，新生突变（de novo mutations）是导致自闭症发病风险升高的重要诱因。基于该假说，我们对表现为散发型自闭症的亲子三联体样本进行了全基因组编码区域，即外显子组（exome）测序，其中包含189例新增三联体以及20例既往已报道的三联体。此外，我们还对对应上述新增三联体（n=31）和既往报道三联体（n=19）的50名未受累兄弟姐妹进行了外显子组测序，最终涵盖来自209个家庭的总计677个个体外显子组数据。
本研究结果显示，新生点突变绝大多数源自父系（比例偏差为4:1），且与父亲年龄呈正相关，这与高龄父亲所生育子女患自闭症的风险轻度升高的结论一致。此外，126个最严重或最具破坏性的新生突变中，有39%（49个）定位至一个高度互联的β-连环蛋白/染色质重塑蛋白互作网络，该网络作为自闭症候选基因集的排名具有显著统计学意义。在先证者的外显子组中，我们在CHD8和NTNG1两个基因中观测到复发性蛋白改变突变。针对1703例自闭症先证者的6个候选基因进行突变筛查后，我们在GRIN2B、LAMC3和SCN1A基因中发现了额外的新生蛋白改变突变。结合拷贝数变异（CNV）数据，上述结果表明自闭症存在极强的位点异质性，但同时也为未来的病因发现、诊断与治疗提供了潜在靶点。