Presentation: Child with a suspected overgrowth-intellectual disability syndrome

A four-year-old girl is referred to paediatrics from primary care with a moderate learning disability (delayed motor milestones, some single words but limited sentences) in association with a height over the 98th centile (2.2 standard deviations (2.2SD) above the mean) and a head circumference over the 99.6th centile (3.1SD above the mean). She has subtle dysmorphic features, including up-slanting palpebral fissures, dolichocephaly and frontal bossing.

Genomic testing should be considered if:

• the patient’s height and/or head circumference is at least 2SD above the mean;
• the patient has dysmorphic features;
• the patient has developmental delay without a clear aetiology; and/or
• a specific overgrowth-intellectual disability (OGID) syndrome is clinically suspected. A number of OGID syndromes have been documented, including Sotos syndrome, Weaver syndrome, Tatton-Brown-Rahman syndrome and CHD8 overgrowth syndrome.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which contains 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 disorders, there are a number of available panels, including:
  • R29 Intellectual disability: This will investigate chromosomal and single-gene causes of developmental delay and/or intellectual disability (the test includes microarray and a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability); and
  • R27 Paediatric disorders (children with a suspected OGID are usually tested under this category): This test includes microarray and a WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics services.
• Note that other panels may also be appropriate – if, for instance, a diagnosis of Beckwith Wiedemann syndrome is suspected, or there is regional (rather than generalised) overgrowth:
  • R50 Isolated hemihypertrophy or macroglossia (methylation testing and multiplex ligation-dependent probe amplification (MLPA);
  • R110 Suspected segmental overgrowth disorders (small panel and MLPA); and/or
  • R263 Confirmation of uniparental disomy (uniparental disomy testing).
• 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 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 R50, R110 and R263:
  • 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 (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.

For clinicians

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

References:

• Tatton-Brown K, Loveday C, Yost S and others. ‘Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability’. American Journal of Human Genetics 2017: volume 100, issue 5, pages 725–736. DOI: 10.1016/j.ajhg.2017.03.010

For patients

• Royal College of Paediatrics and Child Health: Growth charts – information for parents and carers