Familial Amyloidosis (Finnish Type) via the GSN Gene

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).

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).

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.

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).