Institute of Genomic Medicine
Fragile X Syndrome
BACKGROUND:
Fragile X syndrome (FX), also known as Martin Bell syndrome, is the most common cause of inherited mental retardation. It is an X-linked disorder with variable penetrance in which both males and females are affected. Fragile X syndrome is caused by a large expansion of a CGG triplet repeat region of the FMR-1 gene. The number of the CGG repeats correlates with carrier/affected status. Approximately 1:1250 males and 1:2000 females are mentally retarded due to FX. Carrier frequency in females is about 1:260.
INDICATIONS FOR TESTING:
- Males or females who have one or more of the following:
- Mental retardation of unknown etiology.
- A broad range of behavioral or emotional abnormalities: hyperactivity, learning disabilities, language or motor developmental delay, autism or autistic-like symptoms.
- Physical features including a long face with prominent jaw, large ears and macro-orchidism. Many affected individuals, especially children, do not present with these features.
- Family history of X-linked mental retardation, developmental delay or autism.
- Determination of carrier status for individuals with a family history of Fragile X syndrome.
- Prenatal testing when there is a positive family history.
Note: Unless there is documented evidence of FX in the family, we also recommend that conventional cytogenetic analysis be done, to exclude a cytogenetic etiology.
SAMPLE REQUIREMENTS: |
| Blood: 3-5 ml purple top (EDTA) vacutainer of whole blood inverted several times to mix. Forward within 48 hours at room temperature. Please consult the lab for tissue or body fluid submission. |
| Amniotic Fluid: 10-15 ml amniotic fluid from 14th-17th week of gestation or one confluent T25 flask of cultured cells. Send specimen refrigerated, but not frozen (do not ship on dry ice). Please use an overnight courier service. |
| Test Method: methylation sensitive PCR |
| Turn around time: 5-7 days |
| Report: Results of Fragile X testing |
COUNSELING ISSUES:
- Males with full CGG repeat expansions (greater than 230 CGG) are moderately to severely retarded. Females with full expansions are clinically more variable: 1/3 are mentally normal, 1/3 have learning disabilities and are at risk for a spectrum of behavioral abnormalities such as attention problems, depressive disorders, poor eye contact and social withdrawal, and 1/3 have borderline to mild mental retardation. Carrier females may have premature ovarian failure.
- Males and females with premutation size repeats are clinically normal carriers. Males transmit their CGG repeats relatively unchanged to all their daughters whereas female carriers have variable risks for full expansion in offspring depending upon their original numbers of CGG repeats.
- Males with the premutation are unaffected, but will pass on that unstable gene to their daughters, and so are transmitting males. Females with the premutation tend to have premature ovarian failure, with earlier-than-average menopause.
- There is a region of overlap between the normal and premutation (unstable) carrier CGG repeat region. In rare cases analysis of additional family members may be necessary to distinguish between these two possibilities.
- Approximately 1% of Fragile X cases are due to classical mutations in the FMR-1 gene and do not entail CGG repeat expansion. Thus, for prenatal or presymptomatic testing, it is important to first document the presence of a CGG repeat expansion in an affected family member.
- Among individuals with non-specific mental retardation, 4% have full expansion of the FMR-1 gene and 4% have chromosomal abnormalities other than Fragile X. Therefore, unless there is a documented history of Fragile X in the patient's family, both molecular and conventional cytogenetic studies are recommended.
- Genetic counseling is recommended to assist families in understanding the complex inheritance pattern, the variability of Fragile X syndrome, and the management of medical matters such as mitral valve prolapse and joint laxity.
