Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
Faculty of Medicine, Dentistry and Health Sciences, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
Am J Med Genet A. 2022 Jan;188(1):304-309. doi: 10.1002/ajmg.a.62500. Epub 2021 Sep 21.
The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that post-zygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.
脆性 X 智力低下 1 号基因前突变（PM：55-199CGG）与脆性 X 相关震颤共济失调综合征（FXTAS）相关，当从母亲遗传时，存在向超甲基化完全突变（FM：≥200CGG）扩展的风险，从而导致脆性 X 综合征（FXS）。我们描述了一个从母亲遗传的 PM（77CGG），传递给了一个儿子（103CGG）和一个女儿（220-1822CGG），他们分别患有 FXTAS 和 FXS。携带 PM 的男性表现出正常大小的低水平嵌合体 30 和 37CGG。该男性有两个后代：一个女性是 PM 和 FM（56、157、>200CGG）的嵌合体，另一个在多个组织中仅检测到 37CGG 等位基因，均无临床表型。携带 37CGG 等位基因的女性显示出正常的 FMR1 甲基化和 mRNA 水平，并将这个 37CGG 等位基因遗传给了她的一个女儿，这个女儿也没有受到影响。这些发现表明，合子后父亲的收缩可导致正常大小等位基因的低水平嵌合体，这些正常等位基因在经过两代传递时是有功能的。
