Department of Psychiatry, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06135, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
Exp Mol Med. 2024 Aug;56(8):1750-1762. doi: 10.1038/s12276-024-01284-1. Epub 2024 Aug 1.
Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12-14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology.
人类大脑中的低水平体细胞突变与各种神经疾病有关。然而，低水平脑体细胞突变对自闭症谱系障碍（ASD）的贡献仍知之甚少。在这里，我们对 181 个皮质、小脑和外周组织样本进行了高深度外显子测序，平均读取深度为 559.3x，以鉴定 24 名 ASD 受试者和 31 名对照者的脑体细胞单核苷酸变异（SNV）。我们在每个大脑区域的每个外显子中检测到大约 2.4 个脑体细胞 SNV，变异等位基因频率（VAF）低至 0.3%。突变特征，包括数量、特征和类型，在 ASD 患者和对照组之间没有显著差异。有趣的是，当同时考虑具有低水平脑体细胞 SNV 的基因和具有有害种系 SNV 的 ASD 风险基因时，携带体细胞或种系 SNV 的合并基因集在 ASD 患者中显著参与了与 ASD 相关的病理生理学，包括树突棘形态发生（p=0.025）、智力迟钝（p=0.012）和宫内生长迟缓（p=0.012）。此外，合并基因集在早期和中期胎儿皮质、纹状体和丘脑显示出与 ASD 相关的时空表达（均 p<0.05）。具有合并基因集中有害突变的患者比对照组具有更高的 ASD 风险（优势比=3.92，p=0.025，95%置信区间=1.12-14.79）。本研究结果表明，脑体细胞 SNV 和种系 SNV 可能共同导致与 ASD 相关的病理生理学。
