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 and infant physical screening examination (NIPE, also called the newborn check).

Genomic testing should be considered if a patient presents with:

• moderate to profound developmental delay (DD); and/or
• moderate to profound intellectual disability (ID).

Patients with isolated autism or mild intellectual disability are no longer eligible for genetic testing. This is because the chance of finding an underlying genetic condition in this group is very low.

Should an educational psychology assessment not be available, the following statements provide a guide to determine whether a child would be considered to have mild, moderate or severe DD/ID:

• An individual with a mild intellectual disability would typically have delayed milestones but would attend a mainstream school with some support and live independently, with support, as an adult.
• An individual with a moderate intellectual disability would typically require high-level support in a mainstream school or special educational needs schooling and would live with support as an adult. They would typically exhibit the following:
  • functioning at roughly 33%–66% of their chronological age, with significant ongoing delays in two or more areas (cognition, motor skills, speech and/or social-emotional skills) that often require targeted support or an education, health and care plan (EHCP); and
  • attainment significantly below expected levels in most curriculum areas, despite appropriate interventions; struggle with basic literacy, numeracy, and understanding abstract concepts; and often require a highly differentiated curriculum and specialized support.
• A individual with a severe intellectual disability would typically require special educational needs schooling, have limited speech and would not live independently as an adult.

The presence of additional features may increase the chance of a genomic diagnosis. Recognising these can help determine the most appropriate test and include:

• • behavioural and neurodevelopmental differences, 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 asymmetry;
  • microcephaly or macrocephaly;
  • distinctive 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 for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• 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:
    • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with wider features, such as congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. As well as intellectual disability, this test includes several panels that are associated with a wide range of paediatric disorders.
    • 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 R27.
  • If you suspect a condition with an unusual genetic mechanism you may need to arrange additional genomic testing – 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:
    • R47 Angelman syndrome: This includes methylation testing and multiplex ligation-dependent probe amplification (MLPA).
    • R48 Prader-Willi syndrome: This includes methylation testing and MLPA. See Presentation: Clinical suspicion of Prader-Willi syndrome.
• For tests that do not include WGS, including R47 and R48:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) 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.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, 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 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.
• Most 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). For more information, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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: Disability Living Allowance (DLA) for children (guidance)
• Gov.uk: SEND code of practice: 0 to 25 years (guidance)