Expansion of an FMR1 Grey-Zone Allele to a Full Mutation in Two Generations

Abstract

Fragile X Syndrome is caused by the expansion of an unstable CGG-repeat tract in the 5-UTR of the FMR1 gene , which generally results in transcriptional silencing and consequent absence of the FMR1 protein.To date , the smallest premutation allele reported to expand to a full mutation allele in a single generation is 59 CGG repeats. Here , we report a single-generation expansion to a full mutation allele (male with ϳ538 CCG repeats) from a mother who is a carrier of a premutation allele of 56 CGG repeats. Furthermore, the maternal grandfather was a carrier of a gray (or intermediate)-zone allele (45 to 54 repeats) of 52 CGG repeats. Thus , in this family , a gray-zone allele expanded to the full mutation range in two generations. Interestingly , the two AGG interruptions present in the grandfather's allele were absent in the mother's premutation allele. These observations underscore the need to consider carriers of alleles of greater than 55 CGG repeats as being at risk for transmission of a full mutation allele in a single generation , and those with even smaller alleles in the gray zone as being at risk of having grandchildren with full mutation alleles. Fragile X Syndrome (OMIM #300624) is the most common form of inherited mental impairment and the leading known heritable form of autism.1 The disorder is caused by a trinucleotide (CGG) repeat expansion to greater than 200 repeats (full mutation) in the 5Ј-untranslated region of the fragile X mental retardation 1 (FMR1) gene, which generally results in transcriptional silencing and absence of the FMR1 protein.2,3,4 The fragile X syndrome phenotype includes a large spectrum of involvement including mental retardation, developmental and speech delay, physical abnormalities such as large or prominent ears, long and narrow jaw, connective tissue problems, and macro-orchidism. 5 The behavioral phenotype of fragile X syndrome is also characterized by autistic symptoms in approximately 25% to 33%, including social and communication deficits, stereotypic behavior, social anxiety, withdrawal, hyperarousal, unusual responses to sensory stimuli, gaze aversion, inattention, impulsivity, and hyperactivity. 1,6,7,8,9,10 Transmission of a full mutation occurs exclusively from mothers who are carriers of either a full mutation or a premutation (55 to 200 CGG repeats) FMR1 allele. For mothers who are carriers of premutation alleles, the risk of transmitting an allele in the full mutation range is a function of the repeat length. Nolin and colleagues 11 reviewed the propensity for premutation-to-full mutation expansion in more than 1500 transmissions from female carriers of premutation alleles. They showed that the smallest premutation allele leading to a full mutation offspring in a single generation was 59 CGG repeats, which was observed for two female carriers. For slightly smaller alleles (45 to 54 CGG repeats; "gray zone"), the extent of repeat instability is currently unknown. However, due to the observed repeat instability for alleles in this size range, 12,13,14 gray-zo...

Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers

“…9 More than 94% of alleles >90 CGGs expand to a full mutation, 9 whereas a 56-repeat allele is the smallest known to expand to a full mutation in one generation. 10 Today, many pregnant women are screened for their fragile X carrier status irrespective of family history. In the absence of a family history of fragile X, however, risk assessments are problematic because some newly identified intermediate and small premutation alleles are stably inherited.…”

Distribution of AGG interruption patterns within nine world populations

“…The loss of AGG interruptions appear to have occurred multiple times during human evolution (10) but can be a late event in the mutation pathway that leads to expansion (11). It is rare for AGG interruptions to be lost during transmission, but observation of its occurrence has been reported (12)(13)(14).…”

Molecular genetic testing for fragile X syndrome: laboratory performance on the College of American Pathologists proficiency surveys (2001–2009)

“…The intermediate range ("gray zone") is 45-54 repeats, for which expansion to a full mutation in the next generation has not been described, although there is increased instability compared with normal alleles and small, incremental expansions have been observed. 2 The unstable, premutation range of 55-200 repeats is coupled with an increased risk of POI in females and the late-onset, progressive neurodegenerative condition FXTAS in males and, less often, females. 3 In female premutation carriers, the risk of expansion to a full mutation in the next generation increases with the size of the premutation, with essentially 100% risk with greater than 100 repeats.…”