Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
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DOI：
10.1038/s41588-018-0288-4
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发表时间：
2019-01-01
期刊：
影响因子：
30.8
通讯作者：
Eichler, Evan E.
中科院分区：
文献类型：
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作者：
Coe, Bradley P.;Stessman, Holly A. F.;Eichler, Evan E.
我们结合了从10,927个发育迟缓和自闭症患者中的从头突变（DNM）数据，以鉴定253个候选神经发育疾病基因，这些疾病基因超过了错义和/或可能的基因降解性（LGD）突变。在这些基因中，DNM的124个基因达到外显着性（P <5 x 10（-7））。将这些结果与拷贝数变化（CNV）的发病率数据相交，显示了基因组障碍区域的富集（30/253，似然比（LR） + 1.85，p = 0.0017）。我们鉴定出过多的错义DNM重叠缺失综合征（例如，KIF1A和2q37删除）的基因以及重复综合征，例如16p11染色体中的Recurrent MAPK3错义突变，重复，重复的CHD4 CHD4 CHD4 DENMS中的12p13 Duplicense DNMS中，区域和经常性的WDFY4错义DNM 10q11.23重复区域。对DNM过多的基因的网络分析突出了功能网络，包括纹状体的D1（+）和D2（+）刺神经元中的细胞特异性富集。
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 x 10(-7)) 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.