OBJECTIVE The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population. METHOD The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview-Revised. The authors then combined data from previous studies (N=524) for final analyses. RESULTS A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, NBPF1 and NBPF14 (R2=6.2%). Associations were preferentially found in multiplex versus simplex families. CONCLUSIONS The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.

中文翻译：

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Olduvai（DUF1220）拷贝数与遗传性自闭症经典症状的严重程度之间的第三线性关联。

目的作者先前曾报道过，编码自发性孤独症个体的Olduvai蛋白域亚型（CON1）的序列的拷贝数与社交缺陷和交流障碍的严重程度呈线性关系。在这项研究中，作者使用一种改进的测量方法，在一个独立的群体中复制了这种关联。方法作者从Autism Speaks MSSNG项目获得了215位个体的全基因组序列（WGS）数据和表型数据。他们使用改良的序列读取深度技术从WGS数据中获得了拷贝数。线性混合效应模型用于测试Olduvai CON1拷贝数与症状严重程度之间的关联，该关联通过自闭症诊断访谈修订版进行测量。然后，作者结合了先前研究的数据（N = 524）进行最终分析。结果CON1拷贝数与社会诊断评分（SDS）（β= 0.24）和交际诊断评分（CDS）（β= 0.23）之间存在显着的线性关联。利用这些综合数据，作者们发现CON1剂量与SDS（β= 0.18）和CDS（β= 0.13）有很强的显着联系。作者还暗示了在两个基因NBPF1和NBPF14中发现的Olduvai亚型（R2 = 6.2％）。关联优先发现于Multiplex相对于Simplex家族中。结论Olduvai序列与自闭症严重程度之间存在第三种剂量依赖性关联，尤其是在多重家族中，这提供了有力的证据，表明这种高度复制和检查不足的蛋白结构域家族在遗传性自闭症中起重要作用。