Recessive gene disruptions in autism spectrum disorder
Recessive gene disruptions in autism spectrum disorder
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DOI：
10.1038/s41588-019-0433-8
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发表时间：
2019-07-01
期刊：
影响因子：
30.8
通讯作者：
Yu, Timothy W.
中科院分区：
文献类型：
--
作者：
Doan, Ryan N.;Lim, Elaine T.;Yu, Timothy W.
自闭症谱系障碍（ASD）影响高达1/59的个体（1）。全基因组关联和大规模测序研究强烈暗示ASD中的常见变体（2-4）和罕见的新生变体（5-10）。隐性突变也有牵连（11-14），但他们的贡献仍然不太清楚。在这里，我们证明了在一个大型ASD队列中存在过量的双等位基因功能丧失和破坏性错义突变，约占总病例的5%，包括10%的女性，与女性保护作用一致。我们记录了已知或新出现的隐性神经发育基因（CA 2，DDHD 1，NSUN 2，PAH，RARB，ROGDI，SLC 1A 1，USH 2A）以及其他先前未涉及ASD的基因，包括FEV（FEV转录因子，ETS家族成员）的双等位基因破坏，该基因编码多巴胺能电路的关键调节因子。我们的数据完善了隐性突变对ASD的贡献的估计，并提出了照亮以前未知的生物学途径的新途径。
Autism spectrum disorder (ASD) affects up to 1 in 59 individuals(1). Genome-wide association and large-scale sequencing studies strongly implicate both common variants(2-4) and rare de novo variants(5-10) in ASD. Recessive mutations have also been implicated(11-14) but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1,NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.