Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles

Abstract

Most cases of fragile X syndrome (FXS) result from aberrant methylation of the FMR1 gene. Methylation occurs when the number of tandemly arranged cytosine guanine guanine (CGG)-repeats in the 5 0 end of the transcriptional unit of FMR1 exceeds a certain critical threshold, thought to be between 200 and 400 repeats. Such alleles are referred to as full mutation (FM) alleles. Premutation (PM) alleles, alleles with 55-200 repeats, are generally not aberrantly methylated and in fact mayhave hyperexpression of the FMR1 mRNA. We describe here a male who meets the diagnostic criteria for FXS, who is highly mosaic with a mixture of multiple PM and FM alleles and 50% methylation. However, the methylated alleles are limited to two alleles in the PM range,~165 and~175 repeats respectively, with the FM alleles being unmethylated. This finding has implications for FXS diagnosis as well as for efforts to delete the repeat in individuals with FXS using a CRISPR-Cas9 approach.

Regional rates of brain protein synthesis are unaltered in dexmedetomidine sedated young men with fragile X syndrome: A L-[1-11C]leucine PET study

“…These two subjects were mosaic with alleles in the premutation range and in the > 200 range. In one of these subjects the alleles in the premutation range were methylated ( Hayward et al, 2019 ).…”

Decreased rates of cerebral protein synthesis in conscious young adults with fragile X syndrome demonstrated by L-[1-11C]leucine PET

“…In one mosaic participant, alleles in the premutation range were methylated. 26 All other FXS participants had only alleles with CGG repeat lengths exceeding 200. Full scale IQs of participants with FXS ranged from 44–63, indicating mild to moderate cognitive impairment.…”

Mechanisms of Genome Instability in the Fragile X-Related Disorders

“…Silenced FM alleles do contract [20,58], thus some contractions must be transcription independent. Furthermore, the loss of MMR proteins that are required for expansion results in an increase in contractions in the FXD mouse model.…”

“…This can result in a deficit of FMRP, resulting in a phenocopy of the symptoms seen in FM carriers [8,16]. Contraction events that generate a single allele that is present in all cells presumably occur prezygotically [9,10,15], but contractions can occur post-zygotically, resulting in individuals who are mosaic for different sized alleles [10,11,[17][18][19][20]. It has been estimated that 38% of FM carriers are mosaic for additional FM alleles, PM alleles, or both [21].…”