Presentation: Patient with proximal muscle weakness

A 20-year-old woman attends a neurology clinic. She reports needing to use her hands to push herself out of a chair, finding it hard to walk up the stairs and a heaviness in her arms when she is washing or brushing her hair. On examination, you find that she cannot rise unaided, and has a Trendelenburg gait and proximal upper and lower limb weakness.

• Genomic testing should be considered if a patient presents with proximal muscle weakness and, on the basis of assessment and investigation, acquired causes are thought to be unlikely.
• Testing should also be considered if muscle biopsy demonstrates features of a dystrophy or inherited myopathy.
• If the history and examination are both more in keeping with a well-known genetic muscle condition, such as facioscapulohumeral muscular dystrophy (FHMD), Becker muscular dystrophy or oculopharyngeal muscular dystrophy (OPMD), these can be requested as standalone tests.
• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.
• A genetic diagnosis may have implications for other family members, and can be particularly relevant during a pregnancy. For some genetic conditions, rapid testing is available for the purposes of pregnancy management. Assessment of symptoms during pregnancy and discussion of the patient’s choices regarding prenatal testing may be offered. If the patient or a close relative is pregnant, offer them a referral to the local clinical genetics service for further discussion.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for 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 and/or their family. Testing of the following three panels is undertaken by your local highly specialised service, who will send an accompanying letter in the event of a positive result.
  • R79 Congenital muscular dystrophy. This panel is indicated if the patient’s clinical features on muscle biopsy and/or brain imaging suggest a congenital muscular dystrophy. It is undertaken using whole exome sequencing (WES) or medium panel sequencing.
  • R81 Congenital myopathy. This panel should be used if clinical or muscle biopsy features indicate a congenital myopathy. It is undertaken using WES or medium panel sequencing.
  • R82 Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies. This panel should be used if clinical features indicate a likely limb girdle muscular dystrophy or a genetic condition with overlapping phenotype, such as distal myopathy or myofibrillar myopathy. It is undertaken using WES or medium panel sequencing.
• R381 Other rare neuromuscular disorders. This panel should be used if clinical features are atypical and a broader range of genes need to be considered. It is undertaken using whole genome sequencing (WGS) and short tandem repeat testing for the DMPK and AR genes. Analysis is not currently optimal, so if either myotonic dystrophy type 1 or spinal and bulbar muscular atrophy (also known as Kennedy disease) are suspected, this fact should be stated at referral to prompt additional testing where necessary.
• For tests that do not include WGS, such as R79, R81 and R82, you should use your local Genomic Laboratory Hub test order and consent (record of discussion (RoD)) forms.
• For tests that are undertaken using WGS, such as R381, you will need to:
  • complete an NHS GMS test order form with details of the proband, 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);
  • submit parental samples alongside the child’s sample when testing in children (this is trio testing) to aid interpretation of the proband’s result, 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);
  • complete an NHS GMS RoD form for each person being tested – for example, if you are undertaking trio testing of an affected individual and their parents, you will need three RoD forms (see How to complete a RoD form for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• All of the tests described above are DNA-based, and an EDTA sample (purple-topped tube) is required.
• Information about patient eligibility and test indications were 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

• NHS England: National Genomic Test Directory
• The John Walton Muscular Dystrophy Research Centre: Diagnostic and advisory service for limb girdle muscular dystrophies

For patients

• Muscular Dystrophy UK
• NHS Health A to Z: Muscular dystrophy
• The John Walton Muscular Dystrophy Research Centre: Diagnostic and advisory service for limb girdle muscular dystrophies
• TREAT-NMD Neuromuscular Network: Members of the registry network