Fragile X Syndrome
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Direct answer
Fragile X syndrome is an X-linked disorder caused by expansion of a CGG trinucleotide repeat in the FMR1 gene at Xq27.3, which silences the gene through methylation. It is the commonest single-gene cause of inherited intellectual disability and usually affects males more severely than females. Diagnosis rests on DNA testing for repeat length and methylation, and no curative treatment exists, so care centres on education, speech therapy and behavioural support.
What you must remember
- Gene and repeat: FMR1 at Xq27.3 carries a CGG repeat, with normal alleles below about 45 repeats, premutations of about 55 to 200 and full mutations above 200.
- Methylation: full mutations are usually methylated, which silences FMR1 and reduces the FMRP protein that the gene encodes.
- Facial and physical features: long face, prominent forehead and jaw, large everted ears, joint hyperextensibility and macro-orchidism after puberty.
- Behavioural features: autism-spectrum traits, hyperactivity, gaze avoidance, hand-flapping and sensory sensitivity.
- Transmission: a male premutation carrier passes the premutation to all daughters but to no sons, and expansion usually grows through maternal transmission.
- Premutation disorders: fragile X-associated tremor-ataxia syndrome in older male carriers and fragile X-associated primary ovarian insufficiency in women.
- Diagnosis: PCR-based repeat sizing with methylation analysis is first-line, since routine karyotype is normal.
A stepwise pathway from developmental delay to a fragile X diagnosis
A 5-year-old boy has global developmental delay, poor eye contact and a family history of unexplained intellectual disability in maternal relatives. The pathway below moves from clinical suspicion to counselling.
- Suspect the syndrome. Consider it in a boy with developmental delay and autism-spectrum features, particularly when a long face and large ears are present.
- Order repeat-sizing PCR. The test measures the CGG repeat count in FMR1 and sorts alleles into normal, intermediate, premutation or full mutation.
- Add methylation analysis. Southern blot or methylation-specific PCR confirms silencing of the full mutation, and it also helps in mosaic cases.
- Test the mother. Repeat testing identifies whether she is a premutation or full-mutation carrier, which predicts transmission risk.
- Counsel on inheritance. Daughters of a male premutation carrier are obligate carriers, while a female premutation carrier has a 50 per cent chance of passing it to each child.
- Plan follow-up. Carriers need monitoring for tremor and ataxia in later life and for ovarian insufficiency in women.
Where the exam tries to catch you
Three errors recur on this topic.
- Trap: choosing Down syndrome as the commonest cause of intellectual disability Correct: Down syndrome is the commonest chromosomal cause, whereas fragile X is the commonest single-gene inherited cause.
- Trap: expecting a male premutation carrier to pass the disease to his sons Correct: sons inherit the Y chromosome from their father, so only his daughters receive the premutation.
- Trap: dismissing fragile X in girls because they are often less affected Correct: females can have intellectual disability and behavioural features, and premutation carriers are at risk of ovarian insufficiency.
Frequently asked questions
What CGG repeat count defines a full mutation in fragile X syndrome?
A CGG repeat count above about 200 defines a full mutation in fragile X syndrome, and it is usually accompanied by methylation of the FMR1 promoter. Premutations carry about 55 to 200 repeats, while normal alleles have fewer than about 45. Exact cut-offs vary slightly between laboratories.
Why are males with fragile X syndrome usually more severely affected than females?
Males with fragile X syndrome are usually more severely affected because they have one X chromosome, so a full mutation silences their only active FMR1 gene. Females have a second X chromosome that partly compensates, and skewed X inactivation influences severity. Females can still show intellectual disability or behavioural features.
Which premutation carriers are at risk of late-onset neurological disease?
Older male premutation carriers, usually after the age of 50, are at risk of fragile X-associated tremor-ataxia syndrome, which causes intention tremor, gait ataxia and cognitive decline. Women who carry a premutation can develop fragile X-associated primary ovarian insufficiency. Both sexes therefore need genetic counselling and long-term monitoring.
Which test confirms fragile X syndrome in a boy with developmental delay?
DNA testing confirms fragile X syndrome, using PCR to measure the CGG repeat count in FMR1 and methylation analysis to check for gene silencing. Routine karyotype is normal in fragile X, so chromosome analysis cannot make the diagnosis. Results are reported as normal, premutation or full mutation.