Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta‐analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta‐analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss‐of‐function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non‐previous ASD genes, we prioritized PRPF8 and RBM14. Meta‐analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P‐value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra‐hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199–206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.

中文翻译：

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荟萃分析支持以前和新颖的自闭症候选基因：未开发的巴西队列的结果。

神经发育障碍（NDD）的大型基因组数据库是复杂和异质条件下基因组变异的有用资源，例如自闭症谱系障碍（ASD）。我们通过对超过20,000名NDD患者的研究结果进行了荟萃分析，评估了在分子尚未探索的30个ASD三重奏组（n = 90）中，罕见拷贝数变异（CNV）和外显子从头变异的作用。队列。我们确定了三个致病性CNV：在1q21和17p13上有两个重复，在4q35上有一个删除。CNV的荟萃分析（Ñ =8688案件和Ñ = 3591个对照）通过识别其他16 ASD患者重复确认1q21的关联性。外显子组分析确定了7 de novoASD基因的变体（SFARI列表）：CUL3，CACNA1H和SHANK3中三个功能丧失的致病性变体；KCNB1中的一种错义致病变异; 和ATP10A，ANKS1B和DOCK1中的三个有害错义变体。从非先前的ASD基因的其余12个从头变异中，我们对PRPF8和RBM14进行了优先排序。荟萃分析（n = 13,754先证者；n = 2,299对照）确定了另外6例和2例在PRPF8和RBM14中具有经过验证的从头变异的患者， 分别。通过将从头变异体与先前建立的突变率模型进行比较，PRPF8在多次测试校正之前显示出标称意义（P = 0.039，P值调整为0.079，二项式检验），表明其与ASD相关。我们约有60％的患者出现合并症，估计诊断率为23％（7/30：3个病原体CNV和4个新病原体）。我们具有四杂种族裔特征的巴西队列研究人员是宝贵的资源，可用于验证和识别可能的新候选基因座。Autism Res 2020，13：199-206。©2019国际自闭症研究会，Wiley Periodicals，Inc.