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Familial Amyloidosis via the APOA1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8867 APOA1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8867APOA181479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Amyloidosis is characterized by abnormal deposition of insoluble beta-pleated sheet aggregates (amyloid) of specific plasma proteins, resulting in disruption of organ and tissue function. Deposition can be localized or systemic, be restricted to a single organ or involve multiple organs respectively. The kidney is frequently affected. Clinically, the presence of proteinuria, renal insufficiency, heart failure, orthostatic hypertension, peripheral neuropathy or unexplained kidney, heart or systemic disease are suspicious for amyloidosis (Picken 2010). Presentation includes a spectrum of symptoms varying from asymptomatic to fatigue, extremity edema, angina or syncope, which is associated with more advanced disease (Leung et al 2012).

Hereditary apolipoprotein A-I mediated amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits (liver, spleen, and kidneys, with occasional involvement of the heart, nerves, larynx, and gastrointestinal tract) and end-stage renal failure as young adults, while others have only laryngeal and/or skin amyloid deposits, which may be of little clinical consequence (Rowczenio et al. 2011). Although the condition may lead to end-stage renal disease and other organ failure, the natural history of the disease is often slow. The substantial phenotypic heterogeneity among patients with identical APOAI variants implies that other genetic and environmental factors influence clinical manifestations and supports the need for molecular testing in patients with apparent localized amyloidosis, particularly involving the larynx or skin.

Genetics

The majority of amyloidosis is somatic in nature, involving deposition of immunoglobulin light chain (AL) as in myeloma or monoclonal gamopathies, or serum amyloid protein (AA) in chronic inflammation. However, a substantial minority of cases are due to inherited changes in amylogenic proteins. (Picken 2010).

Hereditary or familial amyloidosis is a rare autosomal dominant condition that occurs due to heterozygous mutations in several genes including APOA1. APOA1 encodes apolipoprotein A-I (apoA-I) which is a component of high-density lipoprotein (HDL). HDL transports cholesterol and certain fats called phospholipids through the bloodstream from the body tissues to the liver. HDL is often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. The kidney and liver are the major sites of apo A-I catabolism, which is why nephropathy is mostly observed in the presence of APOA1 variants.

About 45 APOA1 variants (missense, nonsense and inframe deletions) have been described to be pathogenic (Joy et al. 2003; Rowczenio et al. 2011). Variants in APOA1 are associated with high-density lipoprotein (HDL) deficiency and familial visceral amyloidosis (both neuropathic and non-neuropathic forms). These phenotypically distinct groups of mutations are uniquely localized in different regions of the apoprotein sequence (Sorci-Thomas and Thomas 2002). No homozygote for an amyloidogenic apo A-I variant has yet been described, suggesting possible lethality.

Clinical Sensitivity - Sequencing with CNV PGxome

Hereditary or familial amyloidosis occurs due to mutations in several genes. While mutations in the transthyretin (TTR) gene are the most common, accounting for ~90% of hereditary (familial) amyloidosis, about 20 mutations have been identified in the APOA1 gene in individuals with amyloidosis. Our full gene sequencing test is expected to detect >99% of APOA1 causative mutations.

Testing Strategy

This test provides full coverage of all coding exons of the APOA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Molecular genetic testing for APOA1 mediated amyloidosis should be considered in individuals with any of the following findings: biopsied tissues confirm amyloid deposition by Congo red staining which demonstrates a characteristic apple-green birefringence under polarized light, no pathogenic variant identified in the transthyretin gene (accounts for 90% of all familial amyloidosis), or amyloid protein typing using either using immunohistochemical staining of an affected tissue biopsy or liquid chromatography and tandem mass spectrometry (LC/MS/MS) of tryptic digests of micro-dissected amyloid plaques (Rowczenio et al. 2011).

Gene

Official Gene Symbol OMIM ID
APOA1 107680
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Human Gene Mutation Database (Bio-base).
  • Joy T, Wang J, Hahn A, Hegele RA. 2003. Apoa1 related amyloidosis: a case report and literature review. Clinical Biochemistry 36: 641–645. PubMed ID: 14636880
  • Leung N, Nasr SH, Sethi S. 2012. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood 120: 3206–3213. PubMed ID: 22948045
  • Picken MM. 2010. Amyloidosis-where are we now and where are we heading? Archives of pathology & laboratory medicine 134: 545–551. PubMed ID: 20367306
  • Rowczenio D, Dogan A, Theis JD, Vrana JA, Lachmann HJ, Wechalekar AD, Gilbertson JA, Hunt T, Gibbs SDJ, Sattianayagam PT, Pinney JH, Hawkins PN, et al. 2011. Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I. The American Journal of Pathology 179: 1978–1987. PubMed ID: 21820994
  • Sorci-Thomas MG, Thomas MJ. 2002. The effects of altered apolipoprotein AI structure on plasma HDL concentration. Trends in cardiovascular medicine 12: 121–128. PubMed ID: 12007737

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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