Furukawa Sawako, Kushima Itaru, Kato Hidekazu, Kimura Hiroki, Nawa Yoshihiro, Aleksic Branko, Banno Masahiro, Yamamoto Maeri, Uematsu Mariko, Nagasaki Yukako, Ogi Tomoo, Ozaki Norio, Ikeda Masashi
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Medical Genomics Center, Nagoya University Hospital, Nagoya, Japan.
Psychiatry Clin Neurosci. 2025 Mar;79(3):87-97. doi: 10.1111/pcn.13767. Epub 2024 Nov 28.
Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis.
WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS).
Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS.
Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.
自闭症谱系障碍（ASD）是一种具有强烈遗传基础的遗传和表型异质性神经发育障碍。本研究对日本ASD三联体进行了首次全面的全基因组测序（WGS）分析，旨在阐明致病变异的临床意义并加深对ASD发病机制的理解。
对57名日本ASD患者及其父母进行了WGS，研究范围从单核苷酸变异到结构变异（SVs）、短串联重复序列（STRs）、线粒体变异和多基因风险评分（PRS）。
总体上在18名患者（31.6%）中鉴定出可能解释观察到的表型的潜在致病变异，在23名合并智力发育障碍（IDD）的患者中有10名（43.5%）鉴定出此类变异。在接受遗传咨询的患者中鉴定出PTEN、CHD7和HNRNPH2的新生变异，这些患者表现出先前报道的表型，包括一名患有ASD且伴有严重IDD和巨头畸形的患者，其携带PTEN L320S变异。对AlphaFold3蛋白质结构的分析表明PTEN内部分子间相互作用可能受到抑制。SV分析鉴定出ARHGAP11B和TMLHE的缺失。在一名有脑炎病史和认知衰退的ASD患者中鉴定出一个致病性新生线粒体变异。对有无义变异和错义变异（错义有害性、PolyPhen-2和约束>1）的基因进行GO富集分析，显示与生长调节和ATP依赖性染色质重塑活性相关。在STR和PRS分析中未获得可报告的结果。
表征ASD的综合遗传结构和表型是揭示其复杂生物学特性的基本步骤。
