Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA 95616, USA.
Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
Genes (Basel). 2024 Mar 3;15(3):331. doi: 10.3390/genes15030331.
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 () gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FM. We report three patients with an unmethylated FM alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.
脆性 X 综合征（FXS）是智力障碍（ID）的主要遗传性病因，也是自闭症的单一基因病因。尽管大多数 FXS 患者和完全突变（FM）患者的脆性 X 信使核糖核蛋白 1（FMR1）基因完全甲基化，但一些患者存在甲基化和/或 CGG 重复大小的嵌合现象，少数患者存在完全未甲基化的 FM 等位基因。完全缺乏甲基化的患者很少见，关于这些个体的认知和行为表型的文献也很少。我们对未甲基化和镶嵌 FM 的个体进行了文献复习。我们报告了三例未甲基化 FM 等位基因的患者，他们没有任何行为或认知缺陷。这是 FM 男性的一种不常见表现，因为大多数未甲基化 FM 且无行为表型的患者不会接受脆性 X 基因检测或 FXS 诊断。我们的病例表明，由于存在产生 FMRP 的较小等位基因，镶嵌型未甲基化 FM 等位基因的男性可能缺乏行为表型。然而，由于 mRNA 的表达增加，这些个体可能比只有前突变的个体更容易患上脆性 X 相关震颤/共济失调综合征（FXTAS）。
