Presentation: Child with suspected autism spectrum disorder

A family attends clinic concerned that their three-year-old son has repetitive speech and does not appear to interact with his peers. Staff at his nursery share the family’s concerns. In clinic, the child does not respond to adult direction but engages in repetitive play and shows sensory seeking behaviour. Tiptoe walking and hand flapping are observed.

Genomic testing should be considered for individuals presenting with unexplained features of autism spectrum disorder (ASD), particularly when the following are present:

• moderate to profound intellectual disability;
• motor developmental delay;
• other medical problems, such as seizures or congenital heart disease;
• unusual growth patterns, such as growth restriction, overgrowth or asymmetric growth;
• microcephaly or macrocephaly;
• distinctive facial features; and/or
• a family history of learning disability (particularly if it followed an X-linked 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, you can access the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.

If you do not suspect a specific defined genetic condition or syndrome

• Whole genome sequencing (WGS) has a low detection rate under these circumstances, so you may wish to undertake the following tests initially.
  • R377 Intellectual disability – microarray only. This will investigate chromosomal causes of unexplained autism or intellectual disability with clinical features not consistent with fragile X syndrome, or where fragile X testing has been previously performed.
  • R53 Fragile X. This includes short tandem repeat (STR) testing of the FMR1 gene. Though fragile X syndrome is a defined genetic condition, it should be considered early in the testing process (even if you do not suspect a specific defined condition) because it is the most common genetic cause of learning disability (features of ASD are seen in 50%–70% of cases).
    • As fragile X syndrome is a triplet repeat expansion disorder, it may not be reliably detected through other forms of testing.
    • See Child with suspected fragile X syndrome for more details about the R53 test indication.
  • Further testing is only likely to be relevant in individuals with more profound intellectual disability associated with congenital anomalies and/or a distinctive appearance. In these circumstances, you may wish to undertake the following additional tests.
    • R29 Intellectual disability. This will investigate chromosomal and single-gene causes of developmental delay or intellectual disability. It includes microarray and a WGS panel of all genes known to cause intellectual disability. Microarray can be de-selected if it has already been performed.
    • 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 potential chromosomal and single-gene causes. It includes microarray and a WGS ‘super panel’ (a panel comprised of several different constituent panels, forming one large panel).
      • Requesting R27 currently requires authorisation from clinical genetics services.

If you do suspect a specific defined genetic condition or syndrome

• For a list of clinically recognisable conditions in which ASD is a known feature, see our dedicated Knowledge Hub resource.
• Certain conditions, such as imprinting disorders or triplet repeat expansion disorders, are not reliably detected through sequencing tests and require additional specialist tests. However, WGS pipelines are currently being optimised to more reliably detect fragile X syndrome. If you have a strong clinical suspicion of one of these conditions, you may wish to undertake these more targeted tests before considering broader testing:
  • R47 Angelman syndrome: this involves methylation testing and multiplex ligation-dependent probe amplification (MLPA);
  • R48 Prader-Willi syndrome: this involves methylation testing and MLPA; and
  • R53 Fragile X syndrome: this involves STR testing.
• If you are considering broader testing, decide which of the panels best suits the needs of your patient or family. For developmental conditions, there are several available panels.
  • R29 Intellectual disability. This will investigate chromosomal and single-gene causes of developmental delay or intellectual disability. It includes microarray and a WGS panel of all genes known to cause intellectual disability. Microarray can be de-selected if it has already been performed.
  • 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 potential chromosomal and single-gene causes. It includes microarray and a WGS super panel.
    • Requesting R27 currently requires authorisation from clinical genetics services.
• • R28 Congenital malformation and dysmorphism syndromes (microarray only). This should be considered if there are clinical features strongly suggestive of a chromosomal cause – for example, individuals with features characteristic of Williams syndrome.
• • R59 Early onset or syndromic epilepsy. This should be considered if there is unexplained epilepsy with intellectual disability, ASD, structural anomalies or unexplained cognitive or memory decline and you suspect a single-gene cause. It includes microarray and a WGS panel.
• For tests that are undertaken using WGS, including R29, R27 and R59, 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).
• For tests that do not include WGS, including R377, R53, R47, R48 and R28:
• • you should 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.
• These tests are DNA based, and an EDTA sample (purple-topped tube) is required.
• 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
• NICE: Autism spectrum disorder in under 19s: Recognition, referral and diagnosis
• NICE: Autism spectrum disorder in under 19s: Support and management

For patients

• Autistica (research charity)
• Ambitious about Autism
• Autism Speaks
• Contact UK: Social care (support for families with disabled children)
• Dimensions UK
• National Autistic Society
• National Autistic Society: Autism services directory
• NHS England: Whole genome sequencing patient information leaflets
• Resources for Autism