Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia.
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
Sci Rep. 2020 Jul 16;10(1):11701. doi: 10.1038/s41598-020-68465-6.
Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-C) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-C subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55-199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-C subscales as outcome measures.
脆性 X 综合征 (FXS) 是由超甲基化的完全突变 (FM) 扩展引起的，其 CGG 重复数≥200，并且 FMR1 mRNA 及其蛋白减少。然而，FM 等位基因的不完全沉默与 FXS 男性中更严重的自闭症特征有关。本研究比较了基于嵌合体和/或 FMR1 mRNA 沉默存在与否分层的 62 名 FXS 男性（3 至 32 岁）的异常行为检查表-社区-FXS 版（ABC-C）评分。还检查了使用实时 PCR 相对标准曲线法评估的 ABC-C 亚量表与 FMR1 mRNA 水平之间的关联。与仅具有 FM 等位基因和完全丧失 FMR1 mRNA 的男性相比，具有 PM（55-199 CGG）和 FM 等位基因嵌合体的 FXS 组的易激惹（p=0.014）和不适当言语（p<0.001）评分较低。PM/FM 嵌合体组与不完全沉默（p=0.002）组相比，不适当言语评分也较低。FMR1 mRNA 水平升高与易激惹（p<0.001）和健康相关生活质量评分降低（p=0.004）相关，但仅在不完全沉默的 FM 单体组中。这些发现表明，在未来的研究和临床试验中，基于 CGG 大小和 FMR1 mRNA 水平的分层可能是必要的，将 ABC-C 亚量表作为结果测量。
