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<p>Autism spectrum disorder (ASD) is a genetically complex neurodevelopmental condition with a high heritability. However, genomic studies of ASD have been underrepresented in East Asian populations, and the molecular yield in ASD cohorts remains modest. Here, we present a whole-genome sequencing analysis of 3109 samples across 1033 Chinese ASD families. By examining a wide spectrum of genetic variation, we identified rare ASD-associated variants in 19.2% of affected individuals, providing a population-specific view of the genetic architecture of ASD. We identify significant enrichment of de novo variants in probands, nominate or strengthen candidate risk genes (e.g., <i>NCL</i>, <i>SPPL3</i>, <i>ADGRB1</i>, <i>SLC9A3</i>, <i>KIF1B</i>) through mutational burden, evolutionary constraint, recurrent missense site, and functional assays, and implicate convergent pathways including protein palmitoylation. By integrating over 40,000 ASD cases across unpublished and published global cohorts, we identify 245 ASD risk genes, including 45 with limited prior evidence and 32 with no prior association. Single-cell transcriptomic profiling of the developing human cortex reveals that ASD risk genes exhibit widespread yet heterogeneous expression across all major cell types, with peak expression in excitatory neurons, particularly intratelencephalic neurons, and enriched expression in microglia (e.g., <i>C1QC</i>, <i>CARD11</i>, <i>SNX13</i>, <i>MEF2C</i>, <i>FOXP2</i>, <i>TCF12</i>, <i>MED13L</i>), suggesting convergent involvement of both synaptic and neuroimmune mechanisms. Together, our findings expand the ASD genetic landscape and suggest convergent pathogenic axes involving transcriptional regulation, synaptic signaling and plasticity, and neuroimmune interactions. This work supports the development of inclusive diagnostic strategies and provides a foundation for mechanistic and intervention exploration in ASD.</p>

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Genomic landscape of rare variants in a Chinese autism cohort and discovery of novel risk genes

  • 期刊论文

  • 发表日期：

    2026年7月16日

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  • Senwei Tan,
  • Yongqing Lyu,
  • Xiaoyue Sun,
  • Ruolan Guo,
  • Xiaolei Zhang,
  • Zhuo Song,
  • Kewen Chen,
  • Chenzhang Li,
  • Yi Zheng,
  • Canhui Jiang,
  • Cai Qin,
  • Ting Bai,
  • Guizhi Tang,
  • Juan Li,
  • Zhigao Long,
  • Qian Pan,
  • Jieqiong Tan,
  • Ningxia Zhao,
  • Yan Hao,
  • Yu Zhang,
  • Yidong Shen,
  • Jianjun Ou,
  • Yonghua Cui,
  • Chanjuan Hao,
  • Xiangbin Jia,
  • Lu Xia,
  • Jinchen Li,
  • Zhengmao Hu,
  • Wei Li,
  • Hui Guo,
  • Kun Xia

摘要

Autism spectrum disorder (ASD) is a genetically complex neurodevelopmental condition with a high heritability. However, genomic studies of ASD have been underrepresented in East Asian populations, and the molecular yield in ASD cohorts remains modest. Here, we present a whole-genome sequencing analysis of 3109 samples across 1033 Chinese ASD families. By examining a wide spectrum of genetic variation, we identified rare ASD-associated variants in 19.2% of affected individuals, providing a population-specific view of the genetic architecture of ASD. We identify significant enrichment of de novo variants in probands, nominate or strengthen candidate risk genes (e.g., NCL, SPPL3, ADGRB1, SLC9A3, KIF1B) through mutational burden, evolutionary constraint, recurrent missense site, and functional assays, and implicate convergent pathways including protein palmitoylation. By integrating over 40,000 ASD cases across unpublished and published global cohorts, we identify 245 ASD risk genes, including 45 with limited prior evidence and 32 with no prior association. Single-cell transcriptomic profiling of the developing human cortex reveals that ASD risk genes exhibit widespread yet heterogeneous expression across all major cell types, with peak expression in excitatory neurons, particularly intratelencephalic neurons, and enriched expression in microglia (e.g., C1QC, CARD11, SNX13, MEF2C, FOXP2, TCF12, MED13L), suggesting convergent involvement of both synaptic and neuroimmune mechanisms. Together, our findings expand the ASD genetic landscape and suggest convergent pathogenic axes involving transcriptional regulation, synaptic signaling and plasticity, and neuroimmune interactions. This work supports the development of inclusive diagnostic strategies and provides a foundation for mechanistic and intervention exploration in ASD.