Pregnancy Risks of Fragile X Syndrome
Women with Fragile X full mutations have a 50% chance of passing the full mutation to their offspring with each pregnancy, while women with premutations have a 50% chance of passing on the fragile X mutation with variable risk of expansion to a full mutation depending on the size of their premutation. 1
Risks Based on Mutation Type
Full Mutation Carriers
- Women with full mutations (>200-230 CGG repeats) have a theoretical 50% chance of passing the full mutation to their offspring with each pregnancy 1
- Full mutations are characterized by hypermethylation and are associated with fragile X syndrome 1
- Pregnancy outcomes in women with full mutations may be affected by their own cognitive status and ability to manage pregnancy care
Premutation Carriers
- Women with premutations (~55 to ~200 CGG repeats) have a 50% chance of passing the fragile X mutation with each pregnancy 1
- The risk of expansion to a full mutation depends on the size of the premutation in the mother 1:
- 3% risk for maternal alleles with 55-59 CGG repeats (1/23 transmissions)
- Risk increases with larger premutation sizes
- ~100% risk for maternal alleles with 90+ CGG repeats 1
- The smallest premutation allele reported to expand to a full mutation in a single generation is 56 repeats 1
- Premutation carriers should be offered prenatal diagnosis for all pregnancies 1
Intermediate/Gray Zone Carriers
- Carriers of intermediate alleles (45-54 CGG repeats) have not been reported to have offspring with full mutations 1
- Minor increases and decreases in repeat number can occur when intermediate alleles are passed on 1
- A gray-zone allele of 52 repeats has been reported to expand to a premutation allele of 56 repeats in one generation, which subsequently expanded to a full mutation in the next generation 1
Pregnancy Outcomes in Fragile X Carriers
- A cross-sectional case-control study found that carriers of fragile X often experienced more bleeding in late pregnancy than the reference group, but otherwise pregnancy outcomes were favorable 2
- There appears to be no need to initiate special fetal monitoring solely because of the fragile X carrier status of the woman 2
- The risk of premutation expansion to full mutation is significantly lower in individuals identified through general prenatal carrier testing compared to those from known fragile X families 3
Factors Affecting Expansion Risk
- The risk of expansion to full mutation may be correlated with:
- In a study of premutation carriers detected through general prenatal screening 3:
- No change in allele size was noted in 79.6% of transmissions
- Expansion within premutation range occurred in 9% of transmissions
- Expansion to full mutation occurred in 11.4% of transmissions, only in carriers with more than 90 repeats
Genetic Counseling and Testing Recommendations
- All women identified as carriers of premutations should be offered prenatal diagnosis for all pregnancies 1, 5
- Some clinicians may offer prenatal diagnosis to women whose reproductive partners carry a premutation 1
- All at-risk family members of known carriers should be offered testing to determine their status 1
- Prenatal screening for fragile X has been shown to be feasible and acceptable, with high uptake rates (85% in one study) 6
- Individuals identified as carriers of intermediate or premutation alleles should be referred for genetic counseling to properly convey risks for allele expansion and discuss possible future risks of fragile X-associated disorders 5
Additional Considerations for Premutation Carriers
- Female premutation carriers are at risk for fragile X-associated primary ovarian insufficiency (FXPOI) 5
- Both male and female premutation carriers are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS) later in life 5
- These adult-onset conditions introduce more complex counseling challenges when carriers are identified through prenatal screening 5