Fragile X testing: who is tested, how the DNA test works and what results mean

Fragile X syndrome is a genetic condition that usually affects males more severely than females. The Genomics Education Programme describes it as an X-linked condition that results in intellectual disability and characteristic features, that it usually presents in early childhood and is the most common inherited cause of intellectual disability in boys. It describes the prevalence as about 1 in 4,000 people of both sexes, with females usually less severely affected.

The cause is a change in the FMR1 gene on the X chromosome. A short stretch of the DNA code, the CGG triplet, is repeated in the gene. In most people the number of repeats is small and stable. In fragile X syndrome the repeat region has expanded beyond 200 repeats, which switches the gene off so that the protein it normally makes is deficient. Testing measures the size of that repeat region.

The clinical picture that leads to testing varies with age. In children, the Genomics Education Programme lists developmental delay and intellectual disability, social communication and behavioural difficulties (including autism, seen in around 50 to 70 percent of cases), and in boys a long, thin face with prominent ears that may only be obvious in older children. Contact describes delayed or distorted speech and language development, repetitive behaviour, attention difficulties and overactivity, and says around thirty per cent of people with fragile X syndrome develop epilepsy.

In adults, testing may be considered in other settings. The Fragile X Society says testing should be considered for women with primary ovarian insufficiency or early menopause and for people, particularly men, in later life with Parkinson's-like symptoms such as tremor, ataxia (unsteady balance and coordination) or cognitive decline. These are the premutation-associated conditions known as fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS).

Testing may also be offered to relatives when a family member is found to carry a change. The Genomics Education Programme notes that if a boy has a full mutation his mother is expected to carry either a premutation or a full mutation and will need further evaluation and testing.

Contact says fragile X is diagnosed by a blood test that uses DNA analysis to test for the change in the gene. A small blood sample is taken in the usual way, and the DNA is analysed in a specialist genetics laboratory. Results usually take longer than routine blood tests.

The Genomics Education Programme adds that, in the past, diagnosing the triplet repeat mechanism needed a specific test, but because of technological advances fragile X can now be reliably diagnosed through whole genome sequencing. If fragile X is suspected clinically, testing will now often use broader genetic tests that also analyse genes associated with other forms of syndromic intellectual disability. The route into testing in the NHS is through a GP, paediatrician or clinical genetics service, depending on who is being tested and why.

The Genomics Education Programme sets out the categories used by genetics laboratories.

A premutation result can come as a surprise, especially when testing was done because of a relative. The Genomics Education Programme says premutation carriers do not have fragile X syndrome and may be entirely asymptomatic, but certain conditions are associated with the carrier status. It gives figures that around 40 to 75 percent of male premutation carriers and 16 to 20 percent of female premutation carriers will develop FXTAS in later life, and that around 25 percent of female premutation carriers will experience FXPOI, accounting for an estimated 3 to 15 percent of all cases of primary ovarian insufficiency.

The Fragile X Society says approximately 1 in 250 females and 1 in 800 males are carriers, and that there is some evidence carriers may be more likely to experience particular mental health, physical health and cognitive challenges. It also says all known cases of fragile X syndrome have arisen when the carrier gene expanded when passed from a mother to her child, and that there are no known cases of expansion from a father to a daughter. A father who carries a premutation passes it to all his daughters but not to his sons, because sons receive his Y chromosome.

The Genomics Education Programme explains that because fragile X is a triplet-repeat disorder it may show anticipation, becoming more severe over subsequent generations in some families, and that the likelihood of a premutation expanding to a full mutation in the children of a female carrier depends on the size of the repeat and on interruptions in its pattern. It says this should be discussed with the clinical laboratory case by case. Variable X-inactivation makes it hard to predict how a female child will be affected.

For these reasons, a result is usually accompanied by genetic counselling. Counselling covers what the result means for the person tested, what it means for relatives who may wish to be tested, reproductive options and where to find support. The Fragile X Society, the UK registered fragile X charity, describes how a diagnosis can open access to educational support, benefits and specialist services, and also stresses the strengths that people with fragile X often show, including humour, memory and sensitivity to the feelings of others.

Contact says there is no cure for fragile X syndrome and that psychological and educational support for children and families is vital, with speech and language therapy for delayed speech and occupational therapy for sensory and coordination difficulties, and behavioural therapy and sometimes medication for hyperactivity and impulsivity. The Genomics Education Programme says management of children with fragile X syndrome is complex and should be delivered by a multidisciplinary team.

On the NHS, testing is requested through a GP, paediatrician or clinical genetics service according to national criteria. Some private providers offer carrier or fragile X testing; if you use one, ask what exactly is being measured (the repeat size, or a wider panel), who will explain the result and whether genetic counselling is included, and share the result with your GP or genetics service because a carrier finding has implications for relatives.