The Fragile X Premutation

Key Points 

The Fragile X premutation does not cause Fragile X syndrome. 

Females with a Fragile X premutation are generally healthy but some may have an increased chance of having: 

• children with Fragile X syndrome 
• fertility problems and/or early menopause 
• a range of other conditions

Risks vary with the size of the premutation, and many women will not develop any symptoms or be affected.  

Intermediate (Grey zone)	40 – 54   CGG repeats	Not generally considered to be associated with Fragile X syndrome or FXPAC. Not reported by all labs.
Fragile X Premutation (carrier)	55- 199   CGG repeats	FXPAC (FXPOI, FXTAS, FXAND, other)
Fragile X Syndrome (Full mutation)	>  200     CGG repeats	Fragile X syndrome (FXS)

Points to be aware of:  

1. 1. The premutation (PM) is an expansion of the FMR1 gene from 55 to 200 CGG repeats and can occur in both males and females.  
      
      
   2. Females with the PM in general do not have developmental delay as seen with Fragile X syndrome. 
      
      
   3. Females with a PM have a 50% chance of passing the genetic change to their offspring. If the premutation expands to over 200 repeats in their offspring, the child can have Fragile X syndrome. This chance increases with the number of CGG repeats of the female. If a female with 55-69 CGG repeats also has ‘AGG interruptions’, their chance of having children with Fragile X syndrome may be lower.  
      
      
   4. All females with the PM can have an unaffected child. Depending on their CGG expansion size and AGG interruptions, some may need to discuss with a genetic counsellor or appropriate medical practitioner reproductive options such as:
      
      • Prenatal testing to see if the FMR1 gene with the normal number of CGG repeats is inherited
      • IVF with pre-implantation Genetic Testing (PGT-M)
      • Donor egg or embryo
      • Surrogacy
      • Adoption.
        
        
   5. Females with the PM have a chance of developing FXPAC (Fragile X Premutation-Associated Conditions). This includes FXPOI, FXTAS, FXAND and a range of general medical conditions:
      
      • FXPOI (Fragile X-associated Premature Ovarian Insufficiency) occurs in approximately 20 – 30% of females with the PM, some of whom will develop early menopause by age 40.  The chance is lower in women with smaller CGG expansions. Because of this risk, females with the PM should seek medical advice regarding FXPOI and discussion of options including egg freezing and timing of pregnancy.
      • FXTAS (Fragile X-associated Tremor/Ataxia Syndrome) is a Parkinsonian-like neurological disorder affecting a percentage of older PM males and less often older PM females. The chance may be lower in women with smaller CGG expansions. 
      • FXAND (Fragile X-associated Neuropsychiatric Disorders) are present in a percentage of females and males and include a range of anxiety disorders, depression, insomnia, OCD, ASD, ADHD, executive function deficits, chronic fatigue and chronic pain conditions. Many of these are ‘subclinical’ conditions ie do not meet the criteria for a definitive disorder per se. 
      • Other general health conditions that may be associated with the premutation include hypertension, thyroid disorders, sleep disorders, migraine and immune-mediated disorders.  

6. 6. Testing of other family members who may carry the gene should be offered with appropriate genetic counselling. In general, biological parents of someone found to carry a Fragile X gene expansion (greater than 55 CGG repeats) are tested first.   If the male parent is found to carry the PM, then he will pass the PM to all of his daughters and none of his sons.  His parents, siblings and relevant cousins should be offered testing.   If the female parent is found to carry the PM, then all her offspring should be offered testing to determine if they have the PM, full mutation or do not carry the gene expansion. Her parents, siblings and relevant cousins should be offered testing. Testing for family members is covered by Medicare. 
      
      
   7. Management and preventive strategies are important for providing advice regarding reproductive options, ovarian insufficiency, movement and psychiatric symptoms and associated psychological issues if present.

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Further information: 

1. 1. Fragile X Association of Australia – www.fragilex.org.au  

2. 2. USA National Fragile X Foundation – https://fragilex.org/understanding-fragile-x/fragile-x-101/premutation-carriers/    

3. 3. Ref: Tassone F, et al Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation. Cells. 2023 Sep 21;12(18):2330. doi: 10.3390/cells12182330 

4. 4. Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A. Fragile X-Associated Neuropsychiatric Disorders (FXAND). Front Psychiatry. 2018 Nov 13;9:564. doi: 10.3389/fpsyt.2018.00564 

5. 5. Johnson K, Herring J, Richstein J. Fragile X Premutation Associated Conditions (FXPAC). Front Pediatr. 2020 May 27;8:266. doi: 10.3389/fped.2020.00266. PMID: 32537445; PMCID: PMC7267017.