Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.
Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.
复制标题
DOI：
10.1371/journal.pone.0291978
复制
发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
运动刻板印象常见于自闭症谱系障碍（ASD）、智力残疾或感觉剥夺的儿童，以及典型发育中的儿童（“原发性”刻板印象，pCMS）。运动刻板症的确切病理生理机制尚不清楚，尽管遗传病因已被提出。在这项研究中，我们对129例pCMS亲子三人组和853例对照三人组（118例病例和750例质控后的对照）进行了全外显子组DNA测序。我们报告了pCMS与对照组相比，从头预测的损伤性DNA编码变异的发生率增加，将KDM5B鉴定为高置信度风险基因，并估计了184个赋予风险的基因。在pCMS先证者中携带从头损伤性变体的基因显示出与Tourette综合征、ASD以及具有高与低刻板评分的ASD先证者中的那些基因的显著重叠。对这些pCMS基因表达模式的探索性分析发现在早期中期胎儿发育期间在皮质和纹状体内聚集。探索性基因本体论和网络分析突出了钙离子转运、去甲基化、细胞信号传导、细胞周期和发育中的功能趋同。继续测序pCMS三人组将确定额外的风险基因，并提供更深入的了解跨越诊断界限的刻板印象的生物学机制。
Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children (“primary” stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.
登录
查看更多内容
影响因子：
14.9
作者：
Dougherty JD;Schmidt EF;Nakajima M;Heintz N
通讯作者：
Heintz N
影响因子：
3.1
作者：
Gal, Eynat;Dyck, Murray J.;Passmore, Anne
通讯作者：
Passmore, Anne
DOI：
10.3174/ajnr.a4547
发表时间：
2016-03
期刊：
AJNR. American journal of neuroradiology
影响因子：
--
作者：
Harris AD;Singer HS;Horska A;Kline T;Ryan M;Edden RA;Mahone EM
通讯作者：
Mahone EM
DOI：
10.1016/j.cortex.2021.05.022
发表时间：
2021-09
期刊：
Cortex; a journal devoted to the study of the nervous system and behavior
影响因子：
--
作者：
Augustine F;Nebel MB;Mostofsky SH;Mahone EM;Singer HS
通讯作者：
Singer HS
DOI：
10.1111/j.1469-8749.2010.03627.x
发表时间：
2010-08-01
影响因子：
3.8
作者：
Freeman, Roger D.;Soltanifar, Atefeh;Baer, Susan
通讯作者：
Baer, Susan