Fragile X Syndrome (FXS) is one of the most common genetic conditions that causes intellectual disability with varying severity. The word “fragile” describes the site of mutation on the X chromosome that appears broken.
Physical Features:
Neuro-behavioural Features:
FXS is caused by an excessive increase of CGG trinucleotide repeats in the FMR1 gene that is located on the X chromosome. The FMR1 gene plays a crucial role in the brain development by producing a protein called the Fragile X Mental Retardation Protein (FMRP).
When there is an excess of CGG trinucleotide repeats in the FMR1 gene, the promotor region of the FMR1 gene is hyper-methylated. The FMR1 gene is then silenced, so no FMRP protein is produced. The absence of FMRP protein disturbs the biological mechanisms involved in learning and memory, resulting in cognitive challenges.
FXS can be diagnosed through molecular testing. A blood test can be conducted to identify and count the number of the CGG trinucleotide repeats in the FMR1 gene. Depending on the number of CGG repeats, the result can be classified into four categories: normal, grey zone, premutation and full mutation.
| Classification of FMR1 allele | ||
|---|---|---|
| No. of CGG Repeats | Category | Potential Clinical Manifestation |
| <45 | Normal | None |
| 45-54 | Grey Zone | None |
| 55-200 | Premutation | Female: Fragile X associated Primary Ovarian Insufficiency (FXPOI) Both male and female: 1. Fragile X associated Tremor/Ataxia Syndrome (FXTAS) 2. Fragile X associated Neuropsychiatric Disorders (FXAND) |
| >200 | Full Mutation | Fragile X Syndrome (FXS) |
Normal people have fewer than 45 CGG repeats. People who have a premutation (55-200 CGG) in the FMR1 gene do not have FXS, but they might develop other FMR1-related disorders. They can also give birth to children with a premutation or full mutation (FXS).
FXS affects an estimation of 1 in 4000 to 7000 males and 1 in 6000 to 11000 females. Males have one X and one Y chromosome, while females have two X chromosomes. Since FXS is an X-linked dominant disease, males are at a higher risk of having developmental delay and intellectual disability (ID) that are more severe than females. While 50% of affected females have normal intellect, the rest may present with a spectrum of delay, ID and autism spectrum disorder.
Father with Premutation + Unaffected Mother
An affected father (XY) can only pass the FMR1 premutation allele to his daughter(s) but not to his son(s). The daughter will become a premutation carrier as the CGG repeats usually remain stable if transmitted from father.
Unaffected Father + Affected Mother
All children regardless of sex have a 50% chance of inheriting the altered gene from an affected mother with one altered X and one normal X chromosome. Most grey zone alleles are stable, whereas premutation alleles may undergo further expansion into full mutations.
Pregnant women who are FMR1 premutation/full mutation carriers can consider prenatal FXS testing through:
Pre-implantation genetic testing (PGT) alongside IVF (in-vitro fertilization) can be used to prevent transmission of FXS to the next generation.
While there is currently no cure for FXS, special education and training are available for children with FXS to acquire essential life skills effectively. These treatment services can enhance verbal communication, motor abilities and social interactions, which can improve the quality of life of FXS patients and their families.
For further enquires, you may contact us.
Department of Clinical Genetics
Address: Specialist Outpatient Clinic, 1/F, Tower B, Hong Kong Children's Hospital, 1 Shing Cheong Road, Kowloon Bay, Kowloon, Hong Kong
Office Tel: 5741 3186
DCG-FXS
JUNE 2024