Familial Amyloidosis (hATTR) via the TTR Gene

Hereditary transthyretin amyloidosis (ATTR) is a protein misfolding disorder leading to deposition of amyloid aggregates resulting in organ dysfunction. ATTR is a slowly progressive disorder which presents in three main forms: neuropathic, leptomeningeal and cardiac. Neuropathic ATTR affects the peripheral and autonomic nervous system resulting in peripheral neuropathy and difficulty controlling bodily functions. Leptomeningeal ATTR affects the central nervous system causing hydrocephalus, ataxia, seizures and loss of intellectual function (Ando et al. 2013. PubMed ID: 23425518). Cardiac ATTR affects the heart resulting in arrhythmia, cardiomegaly or congestive heart failure. Symptom onset occurs in the third to fifth decade of life. ATTR affects about one in 100,000 individuals in the United States. Treatment of patients with ATTR includes possible transplantation, TTR stabilizer drugs, or TTR antisense therapies that reduce TTR synthesis (Adams et al. 2018. PubMed ID: 29972753; Benson et al. 2018. PubMed ID: 29972757; Ando et al. 2013. PubMed ID: 23425518). Genetic testing is helpful in distinguishing ATTR from other forms of amyloidosis and from other neuropathies and cardiomyopathies (Sekijima. 2018. PubMed ID: 20301373).  

Pathogenic variants in the TTR gene account for ~90% of hereditary amyloidosis cases and are inherited in an autosomal dominant manner with incomplete penetrance. Nearly all ATTR cases are inherited. Autosomal recessive ATTR has been reported in a few cases with patients having higher penetrance, severity and earlier onset compared to autosomal dominant cases (Sekijima. 2018. PubMed ID: 20301373). Other genes associated with hereditary amyloidosis include FGA, B2M, LYZ and APOA1.

Missense changes found throughout the TTR gene account for >95% of the causative variants. Specific missense changes are associated with neuropathic, cardiac or leptomeningeal amyloidosis forms, but phenotypic overlap can occur.

There are two primary founder variants c.148G>A (p.Val50Met) and c.424G>A (p.Val142Ile). These variants are also referred to as p.Val30Met and p.Val122Met using legacy nomenclature. The p.Val50Met variant has been found in 1 in 538 northern Portuguese with penetrance of 80% by age 50, 4% of northern Swedes with penetrance of 11% by age 50, and in 1 in 100,000 Nagano Japanese (Ando et al. 2013. PubMed ID: 23425518; Sekijima et al 2018. PubMed ID: 29343286). Neuropathic ATTR is primarily found in individuals with the p.Val50Met variant in early stages with cardiac and kidney dysfunction . Transgenic mice expressing the p.Val50Met variant present with amyloidosis leading to gastrointestinal, cardiac, and kidney dysfunction (Yi et al. 1991. PubMed ID: 1992765). The p.Val142Ile variant is found in ~3.5% of African Americans with age dependent penetrance and has been found in 10% of African Americans over 65 years of age with severe congestive heart failure (Buxbaum and Ruberg. 2017. PubMed ID: 28102864).

The TTR gene encodes transthyretin, which functions in transport of retinol (vitamin A) and thyroxine (thyroid hormone) when present as a homotetramer (Ando et al. 2013. PubMed ID: 23425518). The TTR gene is not essential for viability of tissue culture cells. Homozygous TTR knockout mice have decreased susceptibility to AMPA-induced neurodegeneration (Nunes et al. 2009. PubMed ID: 19595729).

In a study of 79 unrelated cases meeting criteria for TTR hereditary amyloid polyneuropathy of Portuguese or French descent, pathogenic variants were identified in all cases. Portuguese ATTR patients all were heterozygous for the c.148G>A (p.Val50Met) variant with 87.8% cases having a positive family history. The c.148G>A variant was also identified in ~25% of French ATTR patients and was the most frequently identified pathogenic variant. In French ATTR patients, 43.5% had a positive family history (Planté-Bordeneuve et al. 2003. PubMed ID: 14627687). Analytical sensitivity is likely >99% as all reported pathogenic variants in the TTR gene are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TTR 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).