Diagnosis of individuals suspected of having apolipoprotein A-II-associated familial amyloidosis
Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis
Amyloidosis
APOA2
APO2S
APOAII
Apolipoprotein A-II
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.
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 a Renal Diagnostics Test Request (T830)
0.5 mL
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Ambient (preferred) | ||
Frozen | |||
Refrigerated |
Diagnosis of individuals suspected of having apolipoprotein A-II-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.
The hereditary amyloidoses comprise a group of autosomal dominant, late-onset diseases that show variable penetrance. A number of genes have been associated with hereditary forms of amyloidosis, including those that encode transthyretin, apolipoprotein A-I, apolipoprotein A-II, fibrinogen alpha chain, gelsolin, cystatin C, and lysozyme. Apolipoprotein A-I, apolipoprotein A-II, lysozyme, and fibrinogen alpha chain amyloidosis present as non-neuropathic systemic amyloidosis, with renal dysfunction being the most prevalent manifestation. Apolipoprotein A-II amyloidosis typically presents as a very slowly progressive disease. Age of onset is highly variable, ranging from adolescence to the fifth decade. To date, all mutations that have been identified within the APOA2 gene occur within the stop codon and result in a 21-residue C-terminal extension of the apolipoprotein A-II protein.
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. Tissue-based, laser capture tandem mass spectrometry might serve as a useful test preceding gene sequencing to better characterize the etiology of the amyloidosis, particularly in cases that are not clear clinically.
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 apolipoprotein A-II (APOA2) 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 apolipoprotein A-II associated amyloidosis.
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 those encoding transthyretin, lysozyme, fibrinogen alpha chain, apolipoprotein A-I, 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.
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. Ostertage revisited: The inherited systemic amyloidoses without neuropathy. Amyloid 2005;12(2):75-80
3. Benson MD, Liepnieks JJ, Yazaki M, et al: A new human hereditary amyloidosis: The result of a stop-codon mutation in the Apolipoprotein AII gene. Genomics 2001;72:272-277
4. Yazaki M, Liepnieks JJ, Yamashita T, et al: Renal amyloidosis caused by a novel stop-codon mutation in the apolipoprotein A-II gene. Kidney Int 2001;60:1658-1665
5. Yazaki M, Liepnieks JJ, Barats MS, et al: Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop-codon mutation Stop78Arg. Kidney Int 2003;64:11-16
Bidirectional sequence analysis is performed to test for the presence of a mutation in all 3 coding exons of the APOA2 gene.(Unpublished Mayo method)
Varies
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.
81479-Unlisted molecular pathology procedure
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
APO2Z | APOA2 Gene, Full Gene Analysis | 94189-8 |
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.
|
---|---|---|
53003 | Result Summary | 50397-9 |
53004 | Result | 82939-0 |
53005 | Interpretation | 69047-9 |
53006 | Additional Information | 48767-8 |
53007 | Specimen | 31208-2 |
53008 | Source | 31208-2 |
53009 | Released By | 18771-6 |