Familial Amyloidosis via the APOA1 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 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.

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.

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.

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).