Fragile‐X syndrome and skewed X‐chromosome inactivation within a family: A female member with complete inactivation of the functional X chromosome

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Abstract
Fragile X syndrome is the most common form of inherited mental retardation. It is caused by the increase in length of a stretch of CGG triplet repeats within the FMR1 gene. A full mutation (> 200 repeats) leads to methylation of the CpG island and silencing of the FMR1 gene. We present here two sisters that are compound heterozygotes for a full mutation and a 53 repeat intermediate allele, one of them showing mental retardation and clinical features of an affected male (speech delay, hyperactivity, large ears, prominent jaw, gaze aversion), while the other is borderline normal (mild delay). Southern blot and FMRP expression analysis showed that the sister with mental retardation had the normal FMR1 gene totally methylated and no detectable protein, while her sister had 70% of her cells with the normal FMR1 gene unmethylated and normal FMRP levels. We found that the observed phenotypic differences between both sisters who are cytogenetically normal, are caused by extreme skewed X‐chromosome inactivation. Analysis of the extended family showed that most of the other female family members that carry a pre‐mutation or a full mutation showed some degree of skewing in their X‐chromosome inactivation. The presence of several family members with skewed X inactivation and the direction and degree of skewing is inconsistent with a mere selection during development, and suggests a genetic origin for this phenomenon.
Funding Information
  • the Spanish Ministry of Health (FIS00/779)