Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Ontario, Canada.
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Med Genet A. 2021 Apr;185(4):1120-1130. doi: 10.1002/ajmg.a.62086. Epub 2021 Jan 20.
The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.
PER 家族基因在大脑中作为主要的生物钟节律维持机制发挥作用。PER2 基因突变与家族性睡眠相位提前综合征 1 型（FASPS1）有关，最近也与睡眠时相延迟综合征和特发性嗜睡症有关。在自闭症谱系障碍（ASD）患者中检测到 PER2 变异，这些患者没有报告睡眠障碍，这表明生物钟相关基因在 ASD 的病理生理学中起作用。目前尚不清楚这些个体除了 ASD 之外是否还患有未确诊的昼夜节律睡眠障碍。使用 MSSNG 数据库筛选了 5102 名 ASD 患者的全基因组测序数据，以寻找 PER2 中的潜在突变。确定的家族受邀完成睡眠表型分析，包括结构化访谈和两份标准化睡眠问卷：匹兹堡睡眠质量指数和晨晚节律问卷。在 5102 名 ASD 患者中，发现了两个无义突变、一个移码突变和一个新的错义 PER2 变异（0.08%）。这四个变异中，没有一个与诊断为睡眠障碍有关。其中三人报告了过去或正在发生的睡眠障碍，一人具有高度提示 FASPS1 的症状（就像一名没有 ASD 的突变携带者父亲一样）。携带错义变异的个体没有报告睡眠问题。这些个体的 ASD 和认知特征在严重程度和症状上存在差异。研究结果支持 PER2 相关的昼夜节律紊乱在整体睡眠和有时 FASPS1 失调中起作用的可能性。睡眠失调与 ASD 病理生理学之间的关系需要进一步探索。
