Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome
Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome
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DOI：
10.1186/s11689-019-9288-7
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发表时间：
2019-12-26
影响因子：
4.9
通讯作者：
Godler, David E.
中科院分区：
文献类型：
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作者：
Baker, Emma K.;Arpone, Marta;Godler, David E.
背景脆性 X 综合征 (FXS) 是智力障碍和自闭症谱系障碍 (ASD) 的常见原因，通常与 CGG 扩展（称为完全突变（FM：CGG >= 200）、FMR1 启动子 DNA 甲基化增加和基因沉默相关）。同一个体中存在具有甲基化 FM 或较小的非甲基化前突变 (PM: CGG 55-199) 等位基因的细胞的嵌合现象与更好的认知功能相关。这项研究比较了年龄和性别匹配的仅 FM 和 PM/FM 镶嵌个体的智力功能、自闭症谱系障碍特征和适应不良行为。方法 本研究由 126 名 FXS 男性和女性参与者（年龄 1.15 至 43.17 岁）组成，分为仅 FM 组和 PM/FM 镶嵌组（90 名男性，77.8% 仅 FM；36 名女性，77.8% 仅 FM）。通过适合年龄的发育或智力测试来评估智力功能。自闭症诊断观察表第二版用于检查 ASD 特征，而异常行为检查表社区则用于评估适应不良行为。结果 比较男性和女性（仅 FM + PM/FM 镶嵌），男性在所有领域的智力功能均较差 (p < 0.0001)。尽管女性的自闭症特征较少，父母报告的适应不良行为也较少，但在控制智力功能后，这些差异不再显着。与年龄和性别匹配的仅 FM 参与者相比，患有 PM/FM 嵌合体的参与者，无论性别如何，都表现出更好的智力功能和更少的适应不良行为 (p < 0.05)。在控制整体智力功能后，每个性别中纯 FM 和 PM/FM 嵌合体的 ASD 特征相似。结论 患有 FXS 的男性的智力功能显着低于患有 FXS 的女性。然而，在控制智力功能后，自闭症谱系障碍特征和适应不良行为没有显着差异，与嵌合现象的存在或不存在无关。这表明，主要针对认知能力的干预措施可能反过来会降低适应不良行为的严重程度，包括 FXS 中的 ASD 特征。
Background Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG >= 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55-199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. Methods This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. Results Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. Conclusions Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.