Presentation: Child with suspected fragile X syndrome

A mother attends clinic concerned because her five-year-old son’s development is delayed. He has struggled with his speech and language skills, displays autistic-like behaviour and seems to learn more slowly than other members of the family. You note he has a larger head size and more prominent ears.

• Genomic testing should be considered in male or female patients who present with:
  • unexplained developmental delay or learning disability (of at least a moderate degree);
  • speech delay, ranging from mild difficulties to absent speech;
  • autism spectrum disorder;
  • overactivity and impulsiveness;
  • family history of:
    • fragile X syndrome;
    • X-linked neurodevelopmental condition;
    • premature ovarian failure (because of the potential of fragile X-associated primary ovarian insufficiency); and/or
    • ataxia or tremor (because of the potential of fragile X-associated tremor or ataxia syndrome).
• No one individual will have all the features of fragile X syndrome, and some features (such as a long face and macroorchidism) are more common after puberty. More typical features include:
  • relative macrocephaly;
  • a long face;
  • mildly prominent ears with cupping of the upper pinnae (usually only found in older boys);
  • joint hypermobility; and
  • large testes (post-pubertal).

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which panel best suits the needs of your patient or family.
  • As fragile X syndrome is a nucleotide repeat expansion disorder affecting a gene called FMR1, it previously required standalone analysis via (short tandem repeat (STR) testing).
  • However, as the diagnostic yield was found to be so low for this condition, it is not longer available as an isolated test.
  • Instead, WGS pipelines have been optimised to detect fragile X syndrome and therefore testing for this condition can be completed through R29 or R27, as for any other child presenting with unexplained moderate developmental delay/intellectual disability with or without wider systemic features.
  • If you have a strong suspicion of a chromosomal disorder, you may consider:
    • R377 Intellectual disability (microarray only)
  • If you feel the presentation may result from a chromosomal or single-gene disorder, you may consider whole genome sequencing (WGS), which will detect both:
    • R29 Intellectual disability: This will investigate chromosomal and single-gene causes of developmental delay and/or intellectual disability. It is a WGS panel of all genes known to cause intellectual disability.
    • R27 Paediatric disorders: To be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate potential chromosomal and single-gene causes. R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
  • Certain other conditions, such as imprinting disorders, are not reliably picked up by sequencing tests and may require additional specialist tests. For that reason, if the clinical features are strongly suggestive of one of these other conditions, you may wish to request these more targeted tests before considering broader testing:
    • R47 Angelman syndrome (methylation testing and multiplex ligation-dependent probe amplification (MLPA); and
    • R48 Prader-Willi syndrome (methylation testing and MLPA).
  • For tests undertaken using WGS, including R29 and R27, you will need to:
    • complete an NHS GMS test order form with details of the affected child (proband) and their parents. Include details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
    • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
    • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
  • For tests that do not include WGS, including R377, R47 and R48:
    • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
    • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
  • The majority of tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a 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.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Firth HV and Hurst JA. ‘Oxford Desk Reference: Clinical Genetics and Genomics (second edition)’. Oxford University Press 2017, page 399. DOI: 10.1093/med/9780199557509.003.0003
• Smith K, Chandler K, Hindley D and others. ‘Fragile X syndrome testing in the North West’. Archives of Disease in Childhood 2013: volume 98, issue 3, page 239. DOI: 10.1136/archdischild-2012-302934

For patients

• Fragile X Society
• Fragile X Society: Genetics resources
• NHS England: Whole genome sequencing patient information leaflets