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Mental Health

Presentation: Clinical suspicion of fragile X syndrome in an adult with a personal and family history of neurodevelopmental disorder

The X-linked FMR1 gene is associated with fragile X syndrome. Males with the condition have characteristic facial features and intellectual disability; female presentation varies and may include mood disorders. FMR1-related disorders in relatives include ataxia, tremor and early menopause.

Example clinical scenario

A 34-year-old woman presents with a history of autism spectrum disorder (ASD) and mild learning difficulties. She has a diagnosis of social phobia and has been previously treated for a moderate depressive episode. She has not had any prior genomic testing. Questioning reveals a family history of developmental delay and autism in maternal male cousins. Her maternal grandfather was diagnosed with tremor in his sixties and now uses a wheelchair. Her mother had an early menopause.

When to consider genomic testing

Fragile X syndrome is one cause of intellectual disability (ID) and neurodevelopmental disorders. Full FMR1 gene expansions (CGG expansion >200 repeats) cause fragile X syndrome. Affected males typically have characteristic facial features, moderate to severe ID, speech delay/absence and developmental issues including autism and ADHD. Joint hypermobility and macroorchidism post-puberty may be present. Females who carry a full expansion have variable neurodevelopmental features.

Features of FMR1-associated conditions may be absent or less obvious in females. Other features, such as ataxia and early menopause, may be seen in people with smaller expansions (55–200 CGG repeats, sometimes referred to as “premutations”). Patients with a history of unexplained intellectual disability (ID) should be assessed and considered for genomic testing where:

  • the patient is male with unexplained moderate–severe ID; or
  • the patient is female and has unexplained mild–severe ID, speech delay or ASD, plus an additional family history of:
    • early menopause or premature ovarian failure;
    • progressive tremor and ataxia in adult relatives; and/or
    • unexplained developmental delay or learning disability in relatives, particularly in males.

What do you need to do?

  • Take a detailed family history, asking specific questions about infertility/menopause, ataxia or tremor, developmental delay, speech delay, ID and ASD/attention-deficit hyperactivity disorder (ADHD).
  • Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Before initiating any testing, it is important to carefully consent patients, exploring the potential implications for themselves and their relatives. The risks of future health conditions, such as ataxia or early menopause, may not be obvious to families seeking testing in relation to neurodevelopmental concerns. Similarly, a woman who is mildly affected or who has a premutation may not anticipate that she could have a son affected by full fragile X syndrome.
  • Decide which of the panels best suits the needs of your patient/family:
    • For fragile X syndrome, the standard test is R29 or R27 (FMR1 short tandem repeat testing as part of the intellectual disability (R29) or paediatric disorders (R27) panel (whole genome sequencing (WGS)). See ‘Presentation: Child with suspected fragile X syndrome‘.
      • If clinical or family features are suggestive of fragile X syndrome or other FMR1-related condition, consider referral for assessment and testing if indicated. R29 can be ordered by clinical genetics, neurology, metabolic medicine and paediatrics and R27 by clinical genetics, metabolics and paediatrics. Providing details of symptomatic family members may assist with this assessment.
      • Patients who test positive for an FMR1 expansion should be offered genomic counselling and family support through clinical genetics, as well as referrals to specialties including gynaecology or neurology, where symptoms warrant this.
    • Other tests that may be relevant to families with these features include:
      • R377 Intellectual disability – microarray only, if the primary features are of development delay and autistic features. This microarray test can be ordered by psychiatrists.
      • R54 Hereditary ataxia with onset in adulthood panel via WGS may be considered if the primary features are ataxia and tremor. This test can be requested by neurologists for patients with an unexplained ataxia diagnosis.
    • For tests that do not include WGS, including R377:
    • For WGS-based tests, including R27, R29 and R54, you will need to:
    • The majority of tests are DNA-based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient. 

Resources

For clinicians

References:

For patients

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  • Last reviewed: 20/03/2025
  • Next review due: 20/03/2026
  • Authors: Dr Pam Bowman, Dr Matilda Bradford
  • Reviewers: Dr Mary O'Driscoll, The Fragile X Society Research Committee