Fragile X syndrome (FMR1 CGG repeats): genetics, carriers and testing

Fragile X syndrome is an X-linked condition causing intellectual disability and, in some boys, a characteristic appearance. The NHS Genomics Education Programme describes moderate to severe intellectual disability in boys and mild to moderate disability in about half of affected girls, with the other half intellectually in the typical range. Social communication and behavioural difficulties are common, with autism spectrum disorder in 50% to 70% of cases.

In boys the features can include a long thin face with a prominent forehead and chin, a large head, large ears, joint hypermobility and, after puberty, enlarged testes. These may only be noticeable in older children. The Fragile X Society says the condition is the most common inherited cause of learning disability, and that fragile X is thought to underlie up to 1 in 20 cases of autism.

FMR1 contains a short run of the DNA letters C, G, G repeated. Most people have fewer than 41 repeats. The NHS Genomics Education Programme sorts the sizes into four groups, which behave differently, as the table shows. Above 200 repeats the gene is chemically silenced, the FMR1 protein is not made, and fragile X syndrome results. Boys with a full mutation are usually affected, and girls are variably affected, usually less severely.

Intermediate alleles (41 to 54 repeats) cause no problems themselves but can lengthen over generations. Premutation alleles (55 to 200 repeats) do not cause fragile X syndrome in the person who carries them, but they are unstable and the higher the number, especially above about 90, the greater the chance that the repeat expands to a full mutation when passed on by a mother. The programme says the exact chance depends on the size and the number of AAG interruptions and is discussed case by case with the laboratory.

Because the gene is on the X chromosome, women and men pass it on in different ways. The NHS Genomics Education Programme says an affected female has a 50% chance of passing the condition to any child, and an affected male passes it to all his daughters but none of his sons. Expansion is the added complication: a premutation can grow to a full mutation when passed from mother to child. The Fragile X Society states that all known cases of fragile X syndrome have been caused by expansion on passing from a mother to her child, and that there are no known cases of expansion to a full mutation when a father passes it to a daughter.

The programme also describes anticipation, the tendency for the condition to be more severe in later generations of some families, and notes variability in girls caused by differences in X-inactivation, which makes it hard to predict how a girl will be affected. If a boy has a full mutation, his mother is either a premutation carrier or has a full mutation herself and will be offered further testing.

Most premutation carriers have no symptoms, but two conditions are linked to carrying a premutation. Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurological condition of later life. The NHS Genomics Education Programme says around 40% to 75% of male premutation carriers and 16% to 20% of female carriers will develop it. Fragile X-associated primary ovarian insufficiency (FXPOI) affects women under 40 whose ovaries do not work at full capacity and can lead to subfertility and early menopause; around 25% of female premutation carriers experience it, and it accounts for an estimated 3% to 15% of all primary ovarian insufficiency.

The Fragile X Society adds that there is some evidence carriers may be more predisposed to particular mental health, physical health and cognitive challenges, and that testing should be considered for women with primary ovarian insufficiency or early menopause and for people, particularly men, in later life with Parkinson-like symptoms such as tremor, ataxia or cognitive decline.

The Fragile X Society explains that testing is a DNA blood test, usually arranged through a GP or paediatrician and analysed at a genetics centre. It recommends considering fragile X testing for anyone with a learning disability or developmental delay, and for anyone with autism or autistic-like behaviours. The NHS Genomics Education Programme says testing is now often done through broader genetic tests, including whole genome sequencing, that also look at other genes linked to intellectual disability.

A positive result leads to genetic counselling and the construction of a family tree, so that relatives can decide whether to be tested. The Society points out that a diagnosis helps the child to receive appropriate help with education, speech and language and behaviour, and has implications for relatives. It also advises that anyone diagnosed with a karyotype test before the early 1990s, which was less reliable, may wish to consider re-testing.