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. 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 our Knowledge Hub resource ‘Genomic testing in the devolved nations’.
  • 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 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 and multiplex ligation-dependent probe amplification (MLPA). 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 (recommended by Amyloid Centre; 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.
  • You can also request R204 and R413 directly via the National Amyloidosis Centre, which provides a description of the panels.
• For WGS-based tests, including R15, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband). 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);
  • complete an NHS GMS record of discussion form for each person being tested. (This is typically one form for an affected individual, but if you are undertaking trio testing of an affected individual and their parents, you will need to complete three forms.) See how to complete a record of discussion form for support; and
  • submit parental samples alongside the patient’s when offering duo or trio testing (that is, including one or both parents) to aid interpretation. Where this is not possible, for example because the parents are unavailable for testing, the patient’s samples may be submitted alone – as a ‘singleton’.
  • Note: the National Amyloidosis Centre does not directly arrange R15 testing.
• These tests are DNA-based, and an EDTA sample (purple-topped tube) is required.

For clinicians

• GeneReviews: Familial Mediterranean Fever (FMF)
• GeneReviews: TNF Receptor-Associated Periodic Fever Syndrome (TRAPS)
• GeneReviews: Transthyretin amyloidosis
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• National Amyloidosis Centre (Note: for individual diseases, first see information listed below under ‘For patients’)
• NHS England: National Genomic Test Directory
• OMIM (Online Mendelian Inheritance in Man): #105200 (information about ApoA1 amyloidosis)

For patients

• Amyloidosis UK
• The Bridge: Hereditary amyloidosis resources
• Periodic Fever Syndromes from the National Amyloidosis Centre, London