Presentation: Patient with unclassified amyloidosis

A 48-year-old woman is found to have hypertension and heavy proteinuria. A renal biopsy shows glomerular amyloid deposition with no immunoreactants. She is not known to have any predisposing conditions, and investigations for paraproteins and light chain excess are negative.

• The most common acquired causes of renal amyloidosis are AL amyloidosis, which is associated with evidence of monoclonal protein or light chain excess in the urine or blood, and AA amyloidosis, which complicates chronic systemic inflammation. Where there is no, or weak, evidence for AL type or where there is AA amyloidosis without a known underlying chronic inflammatory condition, consider genomic testing.
• The need for genomic testing is reinforced by any of the following:
  • A family history of renal disease, cardiomyopathy, autonomic or peripheral neuropathy, or other unexplained conditions.
  • A long history of recurrent or continuous episodes of unexplained inflammation, with or without a family history, highlighting the possibility of an inherited systemic autoinflammatory disorder complicated by AA amyloidosis.

• 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 about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient/family. For amyloidosis the most relevant panels are:
  • R204 Hereditary systemic amyloidosis: This indication includes a small gene panel. The panel includes genes shown to be causative in more than one family and can be used when the family history and clinical features suggest a hereditary systemic amyloidosis.
  • R413 Autoinflammatory disorders: This is recommended by the National Amyloidosis Centre; it includes a medium-sized panel test/whole exome sequencing (WES).
  • R15 Primary immunodeficiency or monogenic inflammatory bowel disease: This indication includes whole genome sequencing (WGS); testing is alternatively undertaken via WES if required semi-urgently. It should be used if the amyloid is, or could be, of AA type, in the absence of another chronic inflammatory disease, and/or with a suggestive history.
• For tests that do not include WGS, including R204 and R413:
  • you can use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms; or
  • you can also request R204 and R413 directly via the National Amyloidosis Centre, which provides a description of the panels.
• For tests that are undertaken using WGS, including R15, you will need to:
  • complete an NHS Genomic Medicine Service 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 whole genome sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (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 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).
  • The National Amyloidosis Centre does not directly arrange R15 testing.
• 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.
• 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

• GeneReviews: Familial Mediterranean Fever (FMF)
• GeneReviews: Hereditary Transthyretin amyloidosis
• GeneReviews: TNF Receptor-Associated Periodic Fever Syndrome (TRAPS)
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• National Amyloidosis Centre
• NHS England: National Genomic Test Directory
• OMIM: 105200 Amyloidosis, hereditary systemic 2; AMYLD2

For patients

• Amyloidosis UK
• National Amyloidosis Centre: Helping you understand amyloidosis
• The Bridge: Hereditary amyloidosis resources