Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis
Polymerase Chain Reaction (PCR) Amplification/DNA Sequencing
Transthyretin (TTR) Gene
AMYL
TTR (Transthyretin) Gene
Amyloidosis, Familial Amyloidosis
Varies
Specimen preferred to arrive within 96 hours of draw.
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send specimen in original tube.
Additional Information: To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing-Spanish (T826)
2. Molecular Genetics: Congenital Inherited Diseases Patient Information (T521) in Special Instructions
3. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:
-Hematopathology/Cytogenetics Test Request (T726)
-Renal Diagnostics Test Request (T830)
0.5 mL
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Ambient (preferred) | ||
Frozen | |||
Refrigerated |
Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis
The systemic amyloidoses are a number of disorders of varying etiology characterized by extracellular protein deposition. The most common form is an acquired amyloidosis secondary to multiple myeloma or monoclonal gammopathy of unknown significance (MGUS) in which the amyloid is composed of immunoglobulin light chains. In addition to light chain amyloidosis, there are a number of acquired amyloidoses caused by the misfolding and precipitation of a wide variety of proteins. There are also hereditary forms of amyloidosis. Due to the clinical overlap between the acquired and hereditary forms, it is imperative to determine the specific type of amyloidosis in order to provide an accurate prognosis and consider appropriate therapeutic interventions.
The most common hereditary amyloidosis is familial transthyretin amyloidosis; an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene. The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic TTR protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Typically, TTR-associated amyloidosis is progressive over a course of 5 to 15 years and the most common cause of death is cardiomyopathy. Affected individuals may present with a variety of symptoms, including peripheral neuropathy, blindness, cardiomyopathy, nephropathy, autonomic nervous dysfunction, or bowel dysfunction.
More than 90 mutations have now been identified within the TTR gene, which cause TTR-associated familial amyloidosis. Most of the mutations described to date are single base pair changes that result in an amino acid substitution. Some of these mutations correlate with the clinical presentation of amyloidosis. However, several different mutations have been identified which exhibit considerable clinical overlap.
It is important to note that this assay does not detect mutations associated with non-TTR forms of familial amyloidosis. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific mutation in the family before testing at risk individuals.
An interpretive report will be provided.
All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
A small percentage of individuals who are carriers or have a diagnosis of transthyretin (TTR)-associated amyloidosis may have a mutation that is not identified by this method (eg, large genomic deletions/ duplications, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of TTR-associated amyloidosis. For carrier testing, it is important to first document the presence of a TTR gene mutation in an affected family member.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Mutations in other genes, such as lysozyme, apolipoprotein AII, gelsolin, and others, have been shown to cause other forms of familial amyloidosis. Abnormalities in these genes are not detected by this assay.
Technical Limitations:
In some cases, DNA variants of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
Evaluation Tools:
Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.
Unless reported or predicted to cause disease, alterations in protein coding genes that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.
Reclassification of Variants-Policy:
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely pathogenic alterations or variants of uncertain significance that have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.
DNA sequence analysis was performed on 196 specimens (17 patients with a known transthyretin mutation, 48 patients tested by mass spectrometry, 91 patients with amyloidosis, and 40 normal individuals).
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424
2. Benson MD: The hereditary amyloidoses. Best Pract Res Clin Rhematol 2003;17:909-927
3. Eneqvist T, Sauer-Eriksson AE: Structural distribution of mutations associated with familial amyloidotic polyneuropathy in human transthyretin. Amyloid 2001;8:149-168
4. Connors LH, Lim A, Prokaeva VA, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 2003;10:160-184
Bidirectional sequence analysis is performed to test for the presence of a mutation in all coding regions and intron/exon boundaries of the transthyretin (TTR) gene.(Bergen RH 3rd, Zeldenrust SR, Butz ML, et al: Identification of transthyretin variants by sequential proteomic and genomic analysis. Clin Chem 2004;50:1544-1552)
Performed weekly
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
81404-TTR (transthyretin) (eg, familial transthyretin amyloidosis), full gene sequence
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
ATTRZ | TTR Gene, Full Gene Analysis | 94225-0 |
Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
---|---|---|
53018 | Result Summary | 50397-9 |
53019 | Result | 82939-0 |
53020 | Interpretation | 69047-9 |
53021 | Additional Information | 48767-8 |
53022 | Specimen | 31208-2 |
53023 | Source | 31208-2 |
53024 | Released By | 18771-6 |