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Familial Amyloidosis (Finnish Type) via the GSN 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
8101 GSN 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8101GSN81479 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 N. et al. 2012).

The Finnish type of familial systemic amyloidosis (FAF) or hereditary geloslin amyloidosis (HGA) caused by variants in the gelsolin gene is characterized clinically by a unique constellation of features including corneal lattice dystrophy, cranial neuropathy, bulbar signs, and skin changes. Some patients may develop peripheral neuropathy and renal failure (Sethi etal. 2013). The first sign of FAF, which often presents in the third decade of life, is corneal lattice dystrophy resulting from gelsolin amyloid deposition in the eye (Meretoja J. 1973). As the disease progresses, amyloid begins to affect the cranial and peripheral nerves, causing a slowly progressive polyneuropathy (Solomon et al. 2012). Gelsolin amyloid also deposits in the basement membrane of the skin, resulting in dermatologic abnormalities, including cutis laxa, or thickened and loosened skin with reduced elasticity and resilience (Kiuru-Enari et al. 2005).

Genetics

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

Hereditary or familial amyloidosis is a rare autosomal dominant condition that occurs due to heterozygous mutations in several genes, including GSN, which was first described in 1969 by the Finnish ophthalmologist Jouko Meretoja. The estimated number of disease carriers in Finland is almost 1000, and the disease has subsequently been found in many other countries as well. The gelsolin gene is alternatively spliced to form cytoplasmic and secreted variants, and the amyloidogenic fragments derive from aberrant processing of only the secreted form of gelsolin, also known as plasma gelsolin (Kangas et al. 2002). Both forms of the gelsolin protein attach to actin, helping assemble or disassemble actin filaments. It is thought that, through this function, the gelsolin protein regulates the formation of the actin cytoskeleton.

Hereditary geloslin amyloidosis (HGA) is primarily caused by a G654A or G654T mutation in GSN (Kiuru-Enari et al. 2013), changing the aspartate at position 187 to either an asparagine or tyrosine (legacy nomenclature). A recent report has identified a new variant of gelsolin, changing the glycine at position 167 to arginine (legacy nomenclature), resulting in renal amyloidosis (Sethi et al. 2013). The gelsolin gene defect causes expression of variant gelsolin, followed by systemic deposition of gelsolin amyloid (AGel).

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 GSN gene in individuals with amyloidosis. Our full gene sequencing test is expected to detect >99% of GSN causative mutations.

Testing Strategy

This test provides full coverage of all coding exons of the GSN 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 GSN mediated amyloidosis should be considered in individuals with any of the following findings: family history of gelsolin mediated amyloidosis, presence of lattice corneal dystrophy, where biopsied tissues confirm amyloid deposition by Congo red staining which demonstrates a characteristic apple-green birefringence under polarized light, or GSN protein detection using either using immunohistochemical staining of an affected tissue biopsy or liquid chromatography and tandem mass spectrometry of tryptic digests of micro-dissected amyloid plaques (Sethi et al. 2013).

Gene

Official Gene Symbol OMIM ID
GSN 137350
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Amyloidosis, Finnish Type AD 105120

Citations

  • Human Gene Mutation Database (Bio-base).
  • Kangas H, Seidah NG, Paunio T. 2002. Role of proprotein convertases in the pathogenic processing of the amyloidosis-associated form of secretory gelsolin. Amyloid 9: 83–87. PubMed ID: 12440480
  • Kiuru-Enari S, Haltia M. 2013. Hereditary gelsolin amyloidosis. Handb Clin Neurol 115: 659–681. PubMed ID: 23931809
  • Kiuru-Enari S, Keski-Oja J, Haltia M. 2005. Cutis laxa in hereditary gelsolin amyloidosis. Br. J. Dermatol. 152: 250–257. PubMed ID: 15727635
  • 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
  • Meretoja J. 1973. Genetic aspects of familial amyloidosis with corneal lattice dystrophy and cranial neuropathy. Clin. Genet. 4: 173–185. PubMed ID: 4543600
  • Picken MM. 2010. Amyloidosis-where are we now and where are we heading? Archives of pathology & laboratory medicine 134: 545–551. PubMed ID: 20367306
  • Sethi S, Theis JD, Quint P, Maierhofer W, Kurtin PJ, Dogan A, Highsmith EW. 2013. Renal Amyloidosis Associated With a Novel Sequence Variant of Gelsolin. American Journal of Kidney Diseases 61: 161–166. PubMed ID: 22938848
  • Solomon JP, Page LJ, Balch WE, Kelly JW. 2012. Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention. Critical Reviews in Biochemistry and Molecular Biology 47: 282–296. PubMed ID: 22360545

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.
Total Price: $
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