DataSheet2_Systematic analysis of inheritance pattern determination in genes that cause rare neurodevelopmental diseases.xlsx

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.

尽管目前我们对遗传病因学（genetic etiology）及其分子与生理后果的认知已取得诸多进展，但目前仍尚未明确究竟是哪些遗传特征决定了疾病的遗传模式。为解决这一问题，我们开展了全外显子组测序（whole exome sequencing）分析，对1180名出现神经系统症状的韩国患者的遗传变异进行了特征解析。在纳入通过重新分析额外确诊的33例（占比5.9%）病例后，明确致病变异（pathogenic variant）检出率达到了50.8%。在确诊患者中，33.4%的患者携带遗传性变异。在遗传层面，常染色体隐性遗传（autosomal recessive）相关基因的特征为显著富集于代谢过程、肌肉组织构建以及金属离子稳态（metal ion homeostasis）通路。转录组（transcriptome）与互作组（interactome）谱分析结果显示，隐性遗传基因的大脑特异性表达程度更低，且蛋白质-蛋白质相互作用（protein-protein interaction）数量更少。大多数常染色体隐性遗传基因对变异的耐受性更强，且隐性遗传变异的功能预测得分往往低于显性遗传（dominantly-inherited）变异。此外，我们还能够预测隐性变异的携带者频率。我们的研究结果表明，导致神经发育障碍（neurodevelopmental disorder）的基因，依据其遗传模式的不同，拥有截然不同的分子机制与表达模式。此外，计算得到的隐性变异频率可用于稀有神经发育障碍携带者的预筛查。