Fragile X Syndrome
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P128
2025-12-17
69
The fragile X syndrome is the most common heritable form of moderate intellectual disability. The name fragile X refers to a cytogenetic marker on the X chromosome at Xq27.3, a so-called fragile site induced in cultured cells in which the chromatin fails to condense properly during mitosis. The syndrome is inherited as an X-linked disorder with penetrance in females in the 50 to 60% range. The fragile X syndrome has a frequency of 1 in 3000 to 4000 male births; it is so common that it requires consideration in the differential diagnosis of intellectual disability or autism in both males and females.
Like HD, fragile X syndrome is caused by an unstable repeat expansion. However, in this case, a massive expansion of a different triplet repeat, CGG, occurs in the 5′ untranslated region of a gene called FMR1. The normal number of repeats is up to 55, whereas more than 200 (and even up to several thousand) repeats are found in individuals with the “full” fragile X syndrome allele. The syndrome is due to a lack of expression of the FMR1 gene and failure to produce the encoded protein. The expanded repeat leads to excessive methylation of cytosines in the promoter of FMR1. As discussed in Chapter 3, DNA methylation at CpG islands prevents normal promoter function and leads to gene silencing.
Triplet repeat numbers between 55 and 200 constitute an intermediate premutation stage of the fragile X syn drome. Expansions in this range are unstable when they are transmitted from mother to child and have an increasing tendency to undergo full expansion to more than 200 copies of the repeat during gametogenesis in the female but almost never in the male. The risk for expansion increases dramatically with increasing premutation size (Fig. 1). The overall premutation frequency in females in the population is estimated to be greater than 1 in 200.
Fig1. Frequency of expansion of a premutation triplet repeat in FMR1 to a full mutation in oogenesis as a function of the length of the premutation allele carried by a heterozygous female. The risk for fragile X syndrome to her sons is approximately half this frequency because there is a 50% chance a son will inherit the expanded allele. The risk for fragile X syndrome to her daughters is approximately one-fourth this frequency because there is a 50% chance a daughter would inherit the full mutation, and penetrance of the full mutation in a female is ~50%. (From Nolin SL: Familial transmission of the FMR1 CGG repeat, Am J Hum Genet 59:1252-1261, 1996. The University of Chicago Press.)
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