Genetic Counseling. Bibliography

Genetic counseling is probably the most important reason for identifying children and adults with the fragile X syndrome. Once a single individual has been identified, then the whole family pedigree must be evaluated so that carrier females can be identified and counseled appropriately concerning their risk of having subsequent children with the fragile X syndrome. DNA FMR1 testing should be carried out on all individuals in a family tree who are at risk for carrying the premutation or who may be affected by the syndrome; this testing is available at most major medical centers.

Although the fragile X syndrome has a similar incidence to Down syndrome, the recurrence risk in fragile X is far higher. A carrier female has a 50% risk of passing on the FMR1 mutation with each child. If the mother carries the full mutation, her risk of having a significantly affected child is increased compared to a mother who carries the premutation. However, a woman with >90 CGG repeats will pass on the full mutation to her children every time that X chromosome is transmitted. Expansion to a full mutation occurs only when the mutation is passed on by a female. Males who carry the premutation will pass it on only to their daughters. Their sons inherit the Y chromosome, not the X, so sons of carrier fathers are spared from the fragile X syndrome (Fig. 5).

Once a child is diagnosed with fragile X syndrome it is helpful to have the family contact other parents who have children with similar problems related to fragile X. Parent support groups have been established in almost all states. To find a parent support group in your area, contact the National Fragile X Foundation at 1-800-688-8765. In addition, parent educational materials can be obtained through this foundation. It is essential for parents to understand basic issues regarding inheritance of fragile X syndrome.

Males with the fragile X syndrome have the full mutation in their blood and other tissues with the exception of their sperm. The sperm always carries the premutation only. This recent finding suggests that the expansion to the full mutation does not occur in the egg, but instead expansion occurs early on in embryonic development after the cells that are destined to be gametes (sperm or eggs) are separated from the rest of the embryo and protected against the CGG expansion to the full mutation. If males with fragile X syndrome reproduce they would have unaffected sons and all of their daughters would have the premutation, so they would not be cognitively affected by fragile X syndrome. Because of the overall high recurrence risk, it is absolutely essential for medical professionals to identify this disorder, which at the present time is significantly underdiagnosed.

Bibliography. Ashley, C. T., Jr., and Warren, S. T. (1995). Trinucleotide repeat expansion and human disease. Annu. Rev. Genet. 29, 703-728.
Hagerman, R. J., and Cronister, A. (eds.) (1996). “Fragile X Syndrome: Diagnosis, Treatment and Research,” 2nd ed. Johns Hopkins Univ. Press, Baltimore.
Hagerman, R., Staley, L., Brown, W. T., Taylor, A., Meadows, K., Dorn, M., Stoorman, S., Neri, G., Chiurazzi, P., Levitas, A., Spiridigliozzi, G. A., O’Connor, R., Weber, J. D., Braden, M., and Sudhalter, V. (1995). Conference summary: Fourth International Conference on Fragile X and X-Linked Mental Retardation. Sponsored by the National Fragile X Foundation. Dev. Brain Dysfunction, 8, 167-184. Rousseau, F., Heitz, D., Biancalana, V., Blumenfeld, S., Kretz, C., Boue, J., Tommerup, N., Van Der Hagen, C., DeLozier-Blanchet, C., Croquette, M-F., Gilgenkrantz, S., Jalbert, P., Voelckel, M-A., Oberle, I., and Mandel, J-L. (1991). Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. New Eng. J. Med. 325, 1673-1681.
Rousseau, F., Heitz, D., Tarleton, J., MacPherson, J., Malmgren, H. , Dahl, N., Barnicoat, A., Matthew, C., Mornet, E., Tejadu, I. , Maddaline, A., Spiegel, R., Schinzel, A., Marcos, J. A. G., Schorderet, D. F., Schaap, T., Maccioni, L., Russo, S., Jacobs, P. A., Schubart, A. C., and Mandel, J. L. (1994). A multicenter study on genotype-phenotype correlations in the fragile X syndrome using direct diagnosis with probe StB12.3: The first 2253 cases. Am. J. Hum. Genet. 55, 225-237.
Verkerk, A. J., Pieretti, M., Sutcliffe, J. S., Fu, Y. H., Kuhl, D. P., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., Eussen, B. E., van Ommen, G. J., Blonden, L. A. J., Riggins, G. J., Chastain, J. L., Kunst, C. B., Galjaard, H., Caskey, C. T., Nelson, D. L., Oostra, B. A., and Warren, S. T. (1991).
Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905-914.