Fragile X – Related Disorders

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Gene Symbol: FMR1

Chromosomal Locus: Xq27.3
Protein: Fragile X mental retardation 1 protein (FMR1 protein)
Pseudonyms: Fragile X Syndrome, FRAXA, Fragile X-Associated Tremor/Ataxia Syndrome, Fragile X Tremor- Ataxia Syndrome, FXTAS, Fragile X-Associated Primary Ovarian Failure, FXPOF, FMR1-Related Primary Ovarian Insufficiency, FXPOI
2012 AMA Code: 81243
TESTING METHODOLOGY: Mutation-specific polymerase chain reaction (PCR)
  • Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.
  • Min. Collection: 0.7 ml whole blood EDTA.
  • Transport: Blood in EDTA at room temperature, shipped regular next day air (No Saturday delivery; store specimen at 4 °C and ship Monday).
  • Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
  • Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
  • Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask. Maternal blood sample is required for maternal cell contamination studies.
A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 to obtain further information.
Note: Counseling and informed consent are recommended for genetic testing. A consent form is available as a resource but not required.
Prevalence: Fragile X syndrome affects approximately 1 in 4,000 males and 1 in 6,000 females. Carrier rates are reported as 1 in 178 for females and 1 in 400 for males. For other fragile X-related disorders, FXTAS is estimated to affect 1 in 4,848 and FXPOI is estimated to affect 1 in 3,560.
Inheritance: X-linked dominant disorder with reduced penetrance.
Disease Characteristics: Fragile X syndrome occurs in males with a FMR1 full mutation and is characterized by dysmorphic features including a long face and prominent ears, large testes after puberty, moderate intellectual disability and behavioral and speech abnomalities. About 25% to 50% of females with FMR1 full mutations have mild intellectual disability. FXTAS occurs in males (and some females) who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor. FMR1-related POI occurs in females who have an FMR1 premutation.
Molecular Genetic Mechanism: Trinucleotide repeat (CGG) expansion accompanied by abnormal methylation; normal range 5 to 44 repeats, gray zone 45 to 54 repeats, premutation range 55 to 200 repeats, full mutation range >200 repeats
Methods: Gene-specific FMR1 polymerase chain reaction (PCR) and CGG Repeat Primed (RP) PCR followed by capillary gel electrophoresis
Clinical Sensitivity: Assay detects >99% of individuals with Fragile X syndrome, FXTAS and FMR1-related POI
Analytical Sensitivity: 99%
Test Limitations: Methylation status of alleles is not assessed. Full mutations (>200 CGG repeats) are detected but their size must be determined by Southern blotting. Rare diagnostic errors can occur due to primer / probe site mutations or rare polymorphisms.
  • Patients with unexplained developmental delay, intellectual disability or autism
  • Patients with a family history of Fragile X syndrome
  • Carrier status and prenatal diagnosis for females with a family history of Fragile X syndrome
  • Females with premature ovarian insufficiency (POI)
  • Patients older that 50 years with progressive cerebellar ataxia and intention tremor