Expansion of the Fragile X CGG Repeat in Females with Premutation or Intermediate Alleles

Abstract

The CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (approximately 55-200 repeats) and intermediate (approximately 46-60 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutation-by analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleles-we found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 49-54 repeats, 30.9% for 55-59, and 80% for 60-65 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.

Carrier screening in preconception consultation in primary care

“…Therefore, carrier screening in primary care for reproductive risk in women is more relevant as male carriers are not at risk of having children affected with FXS. A repeat range of 45-54 (the 'grey zone' or intermediate allele) can increase to a premutation allele when transmitted through females such that a grandchild could be affected with FXS (Nolin et al 2003). Notably, premutation carriers themselves have an increased risk of mild learning/emotional difficulties and are at a risk of developing a late-onset neurodegenerative condition (fragile X associated tremor/ataxia syndrome; FXTAS) (Hagerman et al 2001;Jacquemont et al 2003).…”

Similar prevalence of expanded CGG repeat lengths in the fragile X mental retardation I gene among infertile women and among women with proven fertility: a prospective study

“…Lower repeat numbers, varying between 55 and 200, are denominated "premutation", whereas those between 45 and 54 are termed as "intermediate" and those between 35 and 44 as "in the high normal range. " The relevance of expanded CGG repeat lengths in otherwise symptom-free carrier women not only resides in transmitting the full mutation to the male offspring, but also in the proportional expansion of intermediate and premutational CGG repeat numbers transmitted to the X chromosome of the female progeny 1 and in fragile X-associated primary ovarian insufficiency (POI). 2 Considering the severity of the syndrome, the frequency of the carrier status and the potential long-term benefits to the daughters knowing about their mother's screening result, the installment of population-based screening programs has been advocated repeatedly.…”

Fragile X syndrome: Diagnostic and carrier testing

“…That is, they usually are not associated with known unstable transmission to a full mutation and/or a relative with fragile X syndrome. Instability may or may not be characteristic of the allele and depends on factors related to the repeat structure (i.e., interruption of CGG repeats by an AGG sequence) and trans-acting factors not yet defined 7–9. Thus, the definitions of premutation and intermediate alleles are blurred.…”

“…However, the risk of expansion of the CGG repeats in a premutation allele to a full mutation overlays the transmission pattern of this syndrome. Expansion of the premutation to the full mutation during transmission through a carrier woman is positively correlated with the size of the woman’s repeat 9. The smallest repeat size to expand to a full mutation in one generation is 59 repeats 9.…”

“…Expansion of the premutation to the full mutation during transmission through a carrier woman is positively correlated with the size of the woman’s repeat 9. The smallest repeat size to expand to a full mutation in one generation is 59 repeats 9. The risk of expansion to the full mutation from carrier men to their daughters is rare, but has been reported 18.…”