Presentation: Child with lymphoedema

A baby girl is born with bilateral swelling of the dorsum of the feet. The pregnancy was uncomplicated and she is otherwise clinically well, with no significant congenital malformations. On subsequent review, when the child is six months old, the bilateral oedema has progressed.

• You should consider genomic testing if the patient has features consistent with lymphoedema, with or without syndromic manifestations, with no known explanation.
• Testing should be carried out in parallel with expert phenotypic assessment – for example, in the specialist lymphoedema services in Derby or at St George’s Hospital in London.

• 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.
• For information on the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If eligibility criteria are met, discuss with/refer to your local inherited cardiac conditions (ICC) clinical service for genomic testing and family screening, including details of confirmation that the patient fulfils the criteria.
• If the patient fulfils diagnostic criteria as detailed in other published guidelines, but these guidelines differ to the eligibility criteria in the test directory, it is appropriate to refer to an ICC clinic for further assessment.
• Genomic investigations for primary lymphoedema include:
  • R136 Primary lymphoedema: This indication is used when patients present with primary lymphoedema of unknown aetiology, with or without syndromic features. It includes whole exome sequencing or gene panel sequencing (medium panel) to detect small variants and copy number variants.
• In patients presenting with asymmetric or localised involvement suggestive of somatic mosaicism, genomic testing of a biopsy of affected tissue may be appropriate following discussion with a specialist lymphoedema service.
• In patients presenting with features that are consistent with Turner syndrome:
  • R26 Likely common aneuploidy: The test is performed by QF-PCR, with confirmation of results by karyotype if atypical.
• Where lymphoedema is one of multiple features of a complex multi-system condition, consider whether broader testing may be indicated. Discussion with clinical genetics may be helpful. For example:
  • R27 Paediatric disorders: This indication involves whole genome sequencing (WGS).
• The majority of genomic tests for primary lymphoedema are currently undertaken on a singleton basis, although samples may be needed from additional family members in order to interpret results.
• For WGS testing (including R27), parental samples would ideally be submitted alongside the patient sample (this is trio testing). Where this is not possible (for example, because the child is in care or a parent is unavailable for testing), the proband may be tested as a singleton.
• It may be helpful to take blood samples and store DNA pending referral to a specialist lymphoedema or clinical genetics service. Forms for DNA storage are available from your local clinical genetics service or Genomic Laboratory Hub (GLH).
• For tests that do not include WGS, including R136 and R26:
  • 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); and
  • submit parental samples alongside the child’s sample 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).
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• In patients with features suggestive of Turner syndrome, consider sending an additional sample in lithium heparin (typically a green-topped tube) in parallel, in case confirmation of diagnosis by karyotype is required.
• 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

• Lymphatic Education & Research Network: St George’s University Hospitals national lymphoedema clinic
• Lymphatic Education & Research Network: Royal Derby Hospital lymphoedema service
• NHS England: National Genomic Test Directory

For patients

• Lymphoedema Support Network
• NHS Health A to Z: Lymphoedema