Fragile X Syndrome Information

1. Epidemiology

Fragile X syndrome is the most common form of inherited mental impairment, affecting roughly 1 in 4,000 males and 1 in 6,000 females (with carrier rates recently reported as 1 in 178 in females and 1 in 400 in males [2]. Other fragile X-related disorders, such as FXTAS (estimated 1 per 4,848 and FXPOI estimated 1 per 3,560), affect a broad population and age range [3]. More than 1 million individuals in the US alone may be impacted by one of the known fragile X disorders, and most of them are undiagnosed.

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2. Genetics

The disease arises from expansion of DNA triplet sequences in the fragile X mental retardation (FMR1) gene when it is passed from parent to child. The number of cytosine-guanine-guanine (CGG) triplet sequences affects the production of a protein which is required for normal neural development. The most common number of CGG repeats in the FMR1 gene is 28 to 32 CGG repeats. Expansion of the number of CGG sequences in the FMR1 gene to more than 200 repeats (full mutation), generally results in inactivation of the gene through methylation of CpG islands. Patients with a full mutation often manifest symptoms of fragile X syndrome such as severe cognitive or intellectual disabilities. More modest expansions between 55 and 200 CGG may be associated with autism spectrum disorders, reproductive disorders in females (FXPOI), and cognitive/motor disorders in both older males and females (FXTAS).

3. Diagnosis, Screening, and Risk of Expansion

A DNA blood test is most often used to diagnose fragile X syndrome and fragile X-related disorders. A polymerase chain reaction (PCR) assay can assess the number of CGG repeats in the FMR1 gene, and the methylation status of full mutations. Although Southern blot analysis has been conventionally used to identify full mutations, recent advances in technology now allow the number of CGG repeats to be rapidly assessed by PCR [4-6].

Improved diagnostic screening is also in development. Routine screening of newborns is particularly relevant because of the promising pathway-based therapeutics for fragile X syndrome [7]. Carrier screening is also a growing interest [2].

In addition to determining the number of CGG repeats, new techniques are under development to identify adenine-guanine-guanine (AGG) sequences which may interrupt the region of consecutive CGG repeats in the FMR1 gene. This information may impact the genetic counseling of women with intermediate and premutation alleles because AGG “interruptions” are thought to confer DNA stability and to reduce the risk of expansion in the next generation [8-11]. Therefore, the risk of CGG repeat expansion for mothers with AGG “interruptions” may be lower than mothers with the same number of repeats but without at least one AGG.

4. Guidlines for Testing

Professional genetic organizations such as the American College of Medical Genetics (ACMG) recommend fragile X testing for developmental delay, autism, and history of mental retardation [12]. Testing for fragile X syndrome is considered a primary rule-out test in assessment of developmental delay and a first tier test for autism [13].

The American College of Obstetricians and Gynecologists issued a committee opinion for fragile X carrier screening [14] and testing to include:

• Women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency
• Women with ovarian insufficiency or failure or elevated follicle-stimulating hormone level before age 40 years without a known cause
• Women who request fragile X carrier screening, regardless of family history
• Prenatal testing for known carriers

For more information on the ACMG clinical practice guidelines click on the link below:

5. Treatment

6. References

1. Hagerman, R.J. and P.J. Hagerman, Fragile X Syndrome: Diagnosis, Treatment, and Research. 3rd ed. Baltimore: The Johns Hopkins University Press. 3-109. 2002.
2. Hantash, F.M., D.M. Goos, B. Crossley, B. Anderson, K. Zhang, W. Sun, and C.M. Strom, FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genet Med, 13(1): p. 39-45.2011.
3. Hagerman, R.J. and P.J. Hagerman, Testing for fragile X gene mutations throughout the life span. Jama, 300(20): p. 2419-21.2008.
4. Lyon, E., T. Laver, P. Yu, M. Jama, K. Young, M. Zoccoli, and N. Marlowe, A simple, high-throughput assay for Fragile X expanded alleles using triple repeat primed PCR and capillary electrophoresis. J Mol Diagn, 12(4): p. 505-11.2010.
5. Chen, L., A. Hadd, S. Sah, S. Filipovic-Sadic, J. Krosting, E. Sekinger, R. Pan, P.J. Hagerman, T.T. Stenzel, F. Tassone, and G.J. Latham, An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis. J Mol Diagn, 12(5): p. 589-600.2010.
6. Filipovic-Sadic, S., S. Sah, L. Chen, J. Krosting, E. Sekinger, W. Zhang, P.J. Hagerman, T.T. Stenzel, A.G. Hadd, G.J. Latham, and F. Tassone, A novel FMR1 PCR method for the routine detection of low abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem, 56(3): p. 399-408.2010.
7. Hill, M.K., A.D. Archibald, J. Cohen, and S.A. Metcalfe, A systematic review of population screening for fragile X syndrome. Genet Med, 12(7): p. 396-410.2010.
8. Eichler, E.E., J.J. Holden, B.W. Popovich, A.L. Reiss, K. Snow, S.N. Thibodeau, C.S. Richards, P.A. Ward, and D.L. Nelson, Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet, 8(1): p. 88-94.1994.
9. Fernandez-Carvajal, I., B. Lopez Posadas, R. Pan, C. Raske, P.J. Hagerman, and F. Tassone, Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn, 11(4): p. 306-10.2009.
10. Kunst, C.B., E.P. Leeflang, J.C. Iber, N. Arnheim, and S.T. Warren, The effect of FMR1 CGG repeat interruptions on mutation frequency as measured by sperm typing. J Med Genet, 34(8): p. 627-31.1997.
11. Zhong, N., W. Ju, J. Pietrofesa, D. Wang, C. Dobkin, and W.T. Brown, Fragile X "gray zone" alleles: AGG patterns, expansion risks, and associated haplotypes. Am J Med Genet, 64(2): p. 261-5.1996.
12. Sherman, S., B.A. Pletcher, and D.A. Driscoll, Fragile X syndrome: diagnostic and carrier testing. Genet Med, 7(8): p. 584-7.2005.
13. Schaefer, G.B. and N.J. Mendelsohn, Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Genet Med, 10(4): p. 301-5.2008.
14. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol, 116(4): p. 1008-10.2010.
15. Healy, D.G., S. Bressman, J. Dickson, L. Silveira-Moriyama, S.A. Schneider, S.S. Sullivan, L. Massey, K.P. Bhatia, K. Shaw, K.P. Bhatia, J. Bomanji, N.W. Wood, and A.J. Lees, Fragile X Syndrome: An Update on Developing Treatment Modalities. ACS Chemical Neuroscience, 2(8): p. 402-410.2011.

7. Additional Resources

For further details on treatment of fragile X syndrome and related disorders: