Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Department of Pharmacology, Creighton University Medical School, Omaha, NE, USA.
Nat Genet. 2019 Jan;51(1):106-116. doi: 10.1038/s41588-018-0288-4. Epub 2018 Dec 17.
We combined de novo mutation (DNM) data from 10,927 individuals with developmental delay and autism to identify 253 candidate neurodevelopmental disease genes with an excess of missense and/or likely gene-disruptive (LGD) mutations. Of these genes, 124 reach exome-wide significance (P < 5 × 10) for DNM. Intersecting these results with copy number variation (CNV) morbidity data shows an enrichment for genomic disorder regions (30/253, likelihood ratio (LR) +1.85, P = 0.0017). We identify genes with an excess of missense DNMs overlapping deletion syndromes (for example, KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Network analyses of genes showing an excess of DNMs highlights functional networks, including cell-specific enrichments in the D1 and D2 spiny neurons of the striatum.
我们结合了 10927 名发育迟缓伴自闭症个体的新生突变（DNM）数据，鉴定出 253 个候选神经发育疾病基因，这些基因存在过多的错义突变和/或可能的基因破坏性（LGD）突变。在这些基因中，有 124 个基因的 DNM 达到外显子组全基因组显著水平（P < 5×10）。将这些结果与拷贝数变异（CNV）发病率数据相交，显示基因组疾病区域富集（30/253，似然比（LR）+1.85，P = 0.0017）。我们鉴定出了一些基因，这些基因的错义 DNM 过度重叠缺失综合征（例如，KIF1A 和 2q37 缺失）以及重复综合征，例如染色体 16p11.2 重复中 MAPK3 错义突变的反复出现、12p13 重复区域中 CHD4 错义 DNM 的反复出现以及 10q11.23 重复区域中 WDFY4 错义 DNM 的反复出现。对显示 DNM 过度的基因进行网络分析，突出了功能网络，包括纹状体 D1 和 D2 棘状神经元中的细胞特异性富集。
