PRENATAL COUNSELING
- Typically, all sons who inherit an expanded, full mutation exhibit features of fragile X syndrome.
- In daughters, however, a full mutation causes a range of features. In daughters with a full mutation, prognostication is limited. Studies indicate that at least 50%, and in some series 75%, have IQs in the borderline or mentally retarded range.
Longitudinal studies of asymptomatic females with full mutations have not been reported. Fathers with premutations pass the FMR-1 gene in a stable fashion to all offspring, occasionally with contraction to a smaller repeat size.
Note that the complex inheritance pattern, with premutations transmitted through both sexes but expansion limited to the maternal X chromosome, can confound interpretation of family histories of mental retardation or developmental delay.
TABLE 2
Number of CGG repeats influences mutation status
| PERCENT RISK OF EXPANSION TO FULL MUTATION (>200 REPEATS) | ||||
|---|---|---|---|---|
| MATERNAL REPEATS | NOLIN, 19962 | PESSO, 20003 | TOLEDANO-ALHADEF, 20014 | NOLIN, 20035 |
| 55–59 | 13 (3/22) | 0 (0/11) | 0 (0/22) | 4 (1/27) |
| 60–69 | 21 (7/34) | 12 (1/8) | 10 (2/20) | 5 (6/113) |
| 70–79 | 58 (59/102) | 50 (1/2) | 17 (1/6) | 31 (28/90) |
| 80–89 | 73 (78/107) | 50 (1/2) | — | 58 (81/140) |
| 90–99 | 94 (83/88) | 100 (1/1) | — | 80 (89/111) |
| 100–200 | 99 (177/179) | 75 (3/4) | — | 98 (194/197) |
| Values presented as percent (n/N). | ||||
| Data modified from Nolin et al. | ||||
Screening populations
Testing for the FMR-1 gene by determining the expansion size is possible via DNA analysis. Most labs utilize both Southern analyses, to measure the degree of methylation, and polymerase chain reaction, to discriminate at a more refined level the subtle differences in repeat sizes that distinguish intermediate and premutation sizes.
Screening the general population for premutations of the FMR-1 gene is not yet the standard of care. However, several authorities advocate fragile X screening among prenatal and preconception populations, given the relatively high rate of the carrier state (1 in 113 to 350), the sensitivity of testing, and the implications for mental retardation and disability in offspring.
In the United States, even assuming a relatively conservative premutation rate of 1 in 300 and an expansion rate of only 11.3%, such testing would be cost-effective, ranging from $99 to $300 per test.6
What are the risks?
Concerns include the implications of intermediate expansions and the substantial patient education needed to convey the risk of expansion to premutation (but not full mutation). No child with a full mutation has been born to a mother with 59 or fewer repeats. Also needing study is the variability of fragile X syndrome in women with a full mutation. These women are at substantial risk for learning impairment, but the degree of disability varies unpredictably.
Prenatal diagnosis requires DNA from amniocytes or chorionic villus sampling. If the latter, follow-up amniocentesis may be needed because methylation begins at variable times during placental development.7
Preimplantation genetic assessment for fragile X premutation carriers has been reported using a system of closely linked markers, circumventing the need to assess onset of methylation abnormalities.
Spectrum of symptoms
Previously, individuals with premutations were considered clinically asymptomatic. However, we now know that phenotypic expression of expansion sizes occurs along a spectrum.
Recent data indicate 2 phenotypes associated with premutations:
- In women, premature ovarian failure, defined as menopause before the age of 40 years, occurs in 13% to 24% of those with premutations of the FMR-1 gene, among families with fragile X syndrome. Conversely, among women with premature ovarian failure, premutations are found in 2% and 14% of sporadic and familial cases, respectively. Further, the size of the premutation may be directly correlated to the risk of premature ovarian failure.
- In men with premutations, a neurologic syndrome of tremors and ataxia is a newly described phenomenon. The fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, neurodegenerative process with Parkinsonism and peripheral neuropathy, and penetrance appears to increase with age.8 The frequency of this diagnosis among older men with premutations is under study.
Fetal RhD genotyping now possible using maternal plasma
Gautier E, Benachi A, Giovangrandi Y, et al. Fetal RhD genotyping by maternal serum analyses: a two-year experience. Am J Obstet Gynecol. 2005;192:666–669.
Moise K. Fetal RhD typing with free DNA in maternal plasma. Am J Obstet Gynecol. 2005;192:663–665.
Fetal RhD typing using free fetal DNA (ffDNA) is routine in the United Kingdom but not yet in this country. Since 1997, when Lo identified ffDNA in maternal plasma,9 numerous studies have focused on the physiology, timing, and clinical application of fetal RhD typing using ffDNA. Previously, the focus was detection of fetal cells in maternal circulation.
