Regulatory de novo mutations underlying intellectual disability.
Regulatory de novo mutations underlying intellectual disability.
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DOI：
10.26508/lsa.202201843
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发表时间：
2023-05
影响因子：
4.4
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中科院分区：
文献类型：
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本研究为胎儿脑特异性增强子的新生突变在智力残疾的病因学中发挥作用提供了提示性证据。智力残疾（ID）患者的遗传病因的一个主要部分仍然未知。蛋白质编码基因中的从头突变（DNMs）解释了高达40%的病例，但对调控DNMs的潜在作用仍知之甚少。我们对21名ID先证者及其未受影响的父母的63个全基因组进行了测序。此外，我们分析了30个先前测序的外显子组阴性ID先证者的基因组。我们发现，与成人脑增强子相比，调节性DNMs选择性地富集在胎儿脑特异性增强子中。含有DNM的增强子与在前额叶皮层中优先表达的基因相关。此外，我们确定了调节神经系统发育相关基因（CSMD 1，OLFM 1和POU3F3）的反复突变的增强子簇。当使用荧光素酶测定时，来自ID先证者的大多数DNM显示等位基因特异性增强子活性。使用CRISPR介导的突变和编辑表观基因组标记，我们表明调控元件处的DNM影响推定靶基因的表达。因此，我们的研究结果提供了新的证据，表明胎儿脑特异性增强子中的DNMs在ID的病因学中起着重要作用。
This study provides suggestive evidence that the de novo mutations in fetal brain-specific enhancers play role in the aetiology of intellectual disability. The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, and POU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.