FMR1-Related Disorders

Fragile X Syndrome (FXS)

FXS, the most common inherited cause of intellectual disability, affects about 1:4,000-6,250 individuals with one X chromosome (typically assigned male sex at birth); clinical features can include varying degrees of cognitive deficits, seizures, and certain characteristic physical issues. Individuals with two X chromosomes (typically assigned female sex at birth) exhibit symptoms at about half the prevalence as individuals with one X chromosome, and symptoms are generally milder in severity. In over 99% of cases, FXS is caused by a full repeat expansion (>200 CGG trinucleotide repeats) in the FMR1 gene.

Fragile X Tremor/Ataxia Syndrome (FXTAS)

FXTAS can occur in individuals with an FMR1 allele in the premutation range (55-200 CGG repeats) and is characterized primarily by intention tremor, cerebellar gait ataxia, and cognitive impairment. Onset of FXTAS is typically between age 60-65 years; for individuals with an FMR1 allele in the premutation range, FXTAS occurs in approximtely 40% of individuals with one X chromosome and 16-20% of individuals with two X chromosomes.

Fragile X-Related Primary Ovarian Insufficiency (FXPOI)

FXPOI can occur in individuals who have ovaries and an FMR1 allele in the premutation range (55-200 CGG repeats) and is characterized by primary ovarian insufficiency prior to the age of 40. FXPOI occurs in approximately 12-28% of individuals who have ovaries and an FMR1 allele in the premutation range.

Note: Individuals with two X chromosomes and an FMR1 allele with <100 CGG repeats could have additional testing to determine probability of allele expansion upon transmission. (see Lab Test Catalog, lab mnemonic [570] for more info).

The Fragile X DNA test performed is the same for FXS, FXTAS, or FXPOI.

Genetic Counseling

Genetic counseling for FMR1-related conditions is complex and challenging. Genetic counseling for patients and families undergoing or considering genetic testing is highly recommended. The laboratory can provide referrals to genetics clinics in the patient’s locale.

Test performed using polymerase chain reaction (PCR) with capillary electrophoresis to detect expansions of the CGG trinucleotide tract in the 5’UTR of the FMR1 gene.

Note: There are rare FMR1 mutations; less than 1% of individuals affected with FXS do not have an FMR1 allele in the full expansion ("full mutation") range but carry a deletion or point mutation in the FMR1 gene. Pathogenic variants other than the typical CGG repeat expansion (e.g., single nucleotide variants, deletions, complex rearrangements) are not detectable by this assay.

FMR1 is located at chromosome Xq27.3. FMR1 alleles are categorized by number of CCG repeats and methylation status:

• Non-expanded (“normal”) allele: up to 44 repeats
• Intermediate (“gray zone”) allele: 45-54 repeats
• Premutation allele: 55-200 repeats
• Full expansion (“full mutation”) allele: over 200 repeats

Acceptable:

1. Whole blood:5 mL lavender top (EDTA) tube or yellow (ACD) top tube or 2 mL microtainer lavender top tube
   
   
2. Extracted DNA from blood, chorionic villi, and amniocytes: 500 ng (concentration >10 ng/uL)
   
   
3. Cultured amniocytes/chorionic villi: MCC is required for testing fetal samples. See MCC OLTG.
   
   
4. Also acceptable, but requires the Genetics Director's approval and a backup culture. Direct chorionic villi and/or TISSUE: Send 20mg of tissue in a sterile tube or RPMI culture media
   
   *NOTE: If a fetal sample (cultured amniocytes or chorionic villi) was received, add MCC to the order. Prenatal testing requires concomitant testing for maternal cell contamination (see Online Test Guide, MCC for ordering and specimen requirements). See Special Instructions.

Unacceptable: Heparin green top tubes, buccal swab

SPS specimen handling:

1. Whole blood sample: store in the refrigerator
   
   
2. Cultured amniocytes/chorionic villi: store at room temperature. Call the Genetics lab upon receipt (206)598-7021.
   
   
3. Extracted DNA: store in the refrigerator