Lab Update 14.2 – Genetic Testing for FMR1 Disorders (including Fragile X Syndrome)

Updated: May 2022
Ampath | ampath.co.za

Overview of FMR1 Disorders

FMR1-related disorders include:

• Fragile X Syndrome (FXS)
• Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
• Fragile X-associated Primary Ovarian Insufficiency (FXPOI)

Fragile X Syndrome (FXS)

• Most common single-gene cause of intellectual disability (ID)
• Estimated prevalence: 1 in 4000 to 1 in 6000
• Caused by CGG triplet repeat expansion in the 5' untranslated region of the FMR1 gene
• Located on the X chromosome, hence X-linked inheritance

Typical CGG repeat counts:

• Normal: <45 repeats
• Intermediate ("grey zone"): 45–54 repeats
• Premutation: 55–200 repeats
• Full mutation (FXS): >200 repeats

Clinical presentation:

In males with full mutation (>200 CGG repeats):

• Developmental delay
• Intellectual disability
• Behavioural issues, often including autism spectrum disorder
• Various physical and medical features

In females heterozygous for the full mutation:

• Highly variable expression
• About 50% have borderline to mild ID and behavioural concerns

FMR1 Premutation (55–200 CGG repeats)

• Does not cause FXS directly
• Carries risk for other FMR1 disorders:

1. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)

• Affects ~40% of males and 8–17% of females with a premutation
• Onset usually after age 50
• Symptoms include:
  • Cerebellar ataxia
  • Parkinsonism
  • Tremor
  • Cognitive impairment
  • Psychiatric symptoms

2. Fragile X-associated Primary Ovarian Insufficiency (FXPOI)

• Occurs in ~20% of female premutation carriers
• Presents with early menopause (<40 years) or infertility

3. Inheritance risks:

• Female premutation carriers are at increased risk of transmitting a full mutation to offspring
• Risk depends partly on CGG repeat size
• Repeat expansion is more likely when transmitted by females than males

Intermediate Range (45–54 CGG repeats)

• Also known as "grey zone"
• Typically not associated with clinical features
• Unlikely to lead to full mutation in immediate offspring
• May carry risk for expansion in future generations

Who Should Be Tested?

FMR1 testing is recommended for individuals with:

• Unexplained developmental delay or ID
• Autism spectrum disorder (ASD)
• Early menopause or infertility (suspected FXPOI)
• Adult-onset ataxia or tremor (suspected FXTAS)
• Family history of FMR1-related disorders

Note: FMR1 expansions are not detected by:

• Karyotyping
• Array CGH
• Most NGS-based panels or exome sequencing

Testing Method

• Test name: FRAX
• Technique: AmplideX® PCR/CE FMR1 assay
• Analyzes CGG repeat count in the FMR1 gene
• Accuracy: ±1 repeat

How it works:

• PCR reaction uses two primers flanking the CGG region
• A third primer binds within the CGG repeat
• Fragment sizes are analyzed with an Applied Biosystems Genetic Analyzer
• Accurately sizes alleles up to 200 CGG repeats and detects full mutations above that

Testing Information

• Laboratory: Ampath Genetics Laboratory, Centurion
• Sample type: 3–5 mL EDTA blood
• Sample condition: Room temperature
• Turnaround time: 2 weeks
• Mnemonic: FRAX

Important Considerations

• Genetic counselling is highly recommended before and after testing
• Counselling addresses implications for:
  • The individual
  • Family members
  • Future reproductive planning

Contact Information

• Ampath Genetics:
  • Phone: 012 678 1350 / 012 678 0645
  • Email: geneticsclinic@ampath.co.za

📌 For further support or referrals, please contact the Ampath Genetics team.