Presentation: Child with developmental delay or intellectual disability

A family attends the paediatric clinic concerned because their three-year-old son’s development is delayed and unexplained. He sat at one year, was walking at two and a half years and, at the age of three, has a few single words but is not joining two words together. He has distinctive facial features and was diagnosed with an atrial septal defect following the detection of a heart murmur at the newborn check.

Genomic testing should be considered if a patient presents with:

• moderate to profound developmental delay;
• moderate to profound intellectual disability; and/or
• patients who may also have additional features that increase the chance of a genomic diagnosis and help determine the most appropriate test, which include:
  • behavioural problems, including autism spectrum disorder;
  • other medical problems, such as seizures;
  • congenital anomalies, such as congenital heart disease;
  • atypical growth patterns (such as growth restriction, overgrowth or asymmetric growth);
  • microcephaly or macrocephaly;
  • dysmorphic features;
  • developmental regression;
  • atypical MRI brain findings; and/or
  • a family history of learning disability (particularly if there is an X-linked inheritance pattern) or of multiple miscarriages.

• 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 of the panels best suits the needs of your patient or family. For developmental conditions there are a number of available panels, including:
  • R377 Intellectual disability – microarray only: This should be considered if you only want to investigate chromosomal causes, which will require a microarray;
  • R29 Intellectual disability: This should be considered if you want to investigate chromosomal and single-gene causes of developmental delay or intellectual disability (the test is a whole genome sequencing (WGS) panel of many genes known to cause intellectual disability); and
  • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. The test involves whole genome sequencing of a large number of panels simultaneously.
• Certain conditions, such as imprinting disorders or nucleotide repeat expansion disorders, are not reliably picked up by sequencing tests and require additional specialist tests. However, WGS pipelines are now optimised to detect Fragile X syndrome and therefore testing for this condition can be completed through R29 or R27.
• If you do suspect a condition with an unusual genetic mechanism you may need to arrange additional genomic testing. For instance imprinting disorders such as Angelman or Prader-Willi syndrome can be missed by WGS depending on the underlying genetic cause. If there is a clinical suspicion of these syndromes, you may wish to undertake more targeted tests before, after or alongside, broader testing such as:
  • R47 Angelman syndrome: includes methylation testing and multiplex ligation-dependent probe amplification (MLPA)); or
  • R48 Prader-Willi syndrome: includes methylation testing and MLPA.
• For tests that are 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, including 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).
  • 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.
• 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 (this includes the tests discussed here). 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
• StatPearls: Developmental delay

For patients

• Contact UK: Developmental delay (support for families with disabled children)
• Contact UK: Social care
• Council for Disabled Children
• Family Fund (charity that raises grants for families with disabled children)
• Gov.uk guidance: Disability Living Allowance (DLA) for children
• Gov.uk guidance: SEND code of practice: 0 to 25 years