FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene

Abstract

Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5′UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full-mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…Unstable alleles were exhibited among the majority of both female and male PM carriers. In addition, diverse allele profiles were displayed between PBMCs and fibroblasts from the same individuals among PM males, in accordance with previous studies [ 90 , 92 , 93 , 94 , 95 ]. Allelic instability affirms the complexity of FMR1 mutations and may relate to diverse phenotypes, including cognitive abilities and behavioral features observed in both FXS and PM disorders [ 96 ], specifically in female carriers of a PM allele with ADHD and depression [ 91 ].…”

“…It is also notable that PM alleles may be unstable and differ across tissue types [ 86 , 90 , 95 , 477 , 478 ], and the repeat size mosaicism of PM/full-mutation alleles is more likely to occur when the predominant PM CGG repeat length is at the upper end of the PM range [ 479 ]. This implies that the CGG expansion can be present at a larger size (e.g., a full mutation) in unmeasured tissues (including the brain).…”

Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

“…Thus, it is possible that any evidence of expansion in human blood, reflects the presence of even more extensive expansion in organs like brain or gonads. Different allele profiles in different tissues have been reported in some PM carriers [32,33,34,35,36,37,38,39] and 2 different studies support the idea that some men have larger expansions with broader σs in sperm relative to blood [40,41]. Differences between allele sizes in blood and in brain or gonads in expansion-prone individuals could lead to an underestimation of the intergenerational expansion risk.…”

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

“…However, if the blood, saliva and brain of this individual share an allele profile, then it may well be that methylated PM alleles contribute significantly to the patient's symptoms. A previous report described an individual with mild FXS‐like symptoms but an IQ in the normal range, who also had a methylated PM allele along with a larger allele that was unmethylated (Fernandez et al, ). However, the clinical phenotype along with Southern blotting data suggests that the methylated allele represents a relatively minor fraction of his FMR1 alleles.…”