Below are some basic information that every genetic counselor should know about Fragile X-associated Disorders. Please refer to the linked articles for a more thorough review of important genetic counseling issues in Fragile X.
Basic facts about Fragile X for Genetic Counselors
- Fragile X is a family of conditions caused by a mutation in the FMR1 gene including:
- Fragile X Syndrome (FXS)
- Fragile X-associated primary ovarian insufficiency (FXPOI)
- Fragile X-associated tremor ataxia syndrome (FXTAS)
- The FMR1 gene at Xq27.3 is a characterized by a trinucleotide CGG repeat in the 5’ untranslated promoter region. A normal FMR1 allele includes up to 45 CGG repeats, an “intermediate” (grey area) FMR1 allele includes 45-54 CGG repeats, a premutation allele includes 55-200 unmethylated CGG repeats and a full mutation allele, which is usually abnormally hypermethylated, includes over 200 CGG repeats.
- Fragile X syndrome, which occurs in approximately 1/4000 individuals, is caused by a full mutation in the FMR1 gene and is the most common form of inherited intellectual disability. Common features include cognitive disability, autism spectrum disorders, avoidance of eye contact, sensory integration difficulties, hyperflexible small joints, large ears, macroorchidism, and hand flapping. Though more severe in males, up to 70% of females with a full mutation can have cognitive, behavioral and/or physical features of fragile X syndrome. Thus, there is a broad range of features of fragile X syndrome in females which includes a spectrum from a normal phenotype to fully affected. Features such ADHD, speech delay and anxiety/social anxiety is common.
- Females with a full mutation are at 50% risk to have offspring with a full mutation. Males with the full mutation have been reported to have sperm with premutation size alleles.
- The premutation allele can be unstable and expand to a full mutation in the children (both male and female) of female premutation carriers. The risk of expansion is related to the number of CGG repeats (smaller premutations have a lower risk to expand to a full mutation than larger ones).
For a full review of expansion risks see: Nolin, S. L., Brown, W. T., Glicksman, A., Houck, G. E., Gargano, A. D., Sullivan, A., et al. (2003). Expansion of the fragile X CGG repeat in females with premutations or intermediate alleles. Am J Hum Genet, 72, 454–464.
- The smallest premutation that has been reported to expand to a full mutation in one generation was 56 CGG repeats.
- Approximately 1/250 females and 1/800 males are carriers of an FMR1 premutation. In male premutation carriers, the premutation is relatively stable, and has not been reported to have expanded to a full mutation in their daughters. Daughters of carrier males are all obligate carriers.
- Most individuals with premutations have normal cognitive functioning, though increased incidence of anxiety, depression and obsessive disorders is reported. There is a small subset of individuals with premutations who have autism, ADHD and other disorders of development. Research is under way to determine the nature of this relationship.
- Fragile X associated primary ovarian insufficiency (FXPOI) occurs in at least 22% of premutation carriers. The spectrum of FXPOI includes elevated FSH levels, infertility, premature ovarian failure (complete cessation of periods before 40) or early menopause. In untested women who have sporadic ovarian insufficiency approximately 2-7 % have an FMR1 premutation and in those with other relatives with ovarian insufficiency the FMR1 premutation incidence is 10-15%.
- Symptoms of FXTAS, a progressive neurodegenerative condition, occur in at least 1/3 of adult (>50 years) male and approximately 5-8% of female premutation carriers.
- Symptoms of FXTAS include intention tremor, ataxia, memory loss, dementia, personality change including irritability and mood swings and it is often misdiagnosed as Parkinson’s, Alzheimer’s, other ataxias, Multiple Sclerosis, or stroke.
- Pedigree information for at risk families should include questions related to:
- Adult onset neurological symptoms described in FXTAS
- Female relatives with infertility, early menopause
- Male and female relatives with developmental, speech, behavioral or learning disorders.
- Reproductive options for carriers include prenatal diagnosis by CVS or amniocentesis, preimplantation genetic diagnosis (PGD) egg or embryo donation, adoption or child free living. PGD is available at a small number of centers and the success of PGD is limited by a number of factors including ovarian dysfunction in the carrier, difficulties with linkage analysis and other factors.
- Laboratories are now reporting intermediate or grey area alleles of 45-54 CGG repeats. These alleles are often stable and do not increase the risk for fragile X associated disorders. In a small number of families these alleles have shown some degree of instability and could potentially expand and lead to a premutation in future generations.
- FMR1 testing presently includes both PCR and southern blot analysis, as PCR doesn not always detect full mutations and methylation status. However new technologies will likely lead to an all PCR based test in the near future.
The NFXF Fragile X-associated Disorders Handbook is a perfect introduction of FXD’s for families.
For a comprehensive review of Fragile X-associated Disorders please see the following recommended readings:
- The FMR1 premutation and reproduction
(Wittenberger, et al)
- Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors
(Finucane, et al)
- Prevalence and Instability of Fragile X Alleles
(Cronister, et al)
- Fragile X-Associated Tremor/Ataxia Syndrome: Clinical Features, Genetics, and Testing Guidelines
(Berry-Kravis, et al)
- Recommendations from Multi-disciplinary Focus Groups on Cascade Testing and Genetic Counseling for Fragile X-associated Disorders
(McConkie-Rosell, et al)
- When to Tell and Test for Genetic Carrier Status: Perspectives of Adolescents and Young Adults From Fragile X Families
(Wehbe et al)
- Advances in the treatment of fragile X syndrome
(Hagerman et al)
For further information or questions please contact the National Fragile X Foundation via phone at (800) 688-8765 or e-mail at firstname.lastname@example.org.