NavigATTR Sponsored Testing Program

Hereditary transthyretin amyloidosis (ATTR) is a protein misfolding disorder that leads to deposition of amyloid aggregates and results in organ dysfunction. Neuropathic ATTR affects the peripheral and autonomic nervous system, resulting in peripheral neuropathy and difficulty controlling bodily functions. ATTR affects about 1 in 100,000 individuals in the United States, but the true prevalence may be higher. Genetic testing is helpful in distinguishing hATTR polyneuropathy from other peripheral neuropathies and from wild-type ATTR cardiomyopathy.

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.

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).

Missense mutations found throughout the TTR gene account for >95% of the causative variants. Specific TTR gene variants are associated with characteristic neuropathic or cardiac phenotypes, but multisystem involvement is typical and a mixed-phenotype is seen in most patients (Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122).

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 agedependent 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).

This test provides full coverage of all coding exons of the TTR gene, plus 10 bases of flanking non-coding DNA in all available transcripts, along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere.

Patients must reside in the United States, be at least 18 years of age, and meet certain other eligibility criteria, as specified on the test requisition form. Eligible patients include adult (>18 years of age) US residents with either family history of hATTR, positive PYP, or biopsy for amyloidosis. Patients with 2+ red-flag symptoms also may qualify. All testing must be ordered by a qualified healthcare professional.

Telehealth genetic counseling with Genome Medical, a national telegenetics care provider, is available at no cost to patients through this sponsored testing program. Genetic counseling via telephone appointment is available for patients to provide information, education, support, and address questions related to sponsored genetic testing and results. You may refer patients for one pre-test or one post-test genetic counseling by checking the appropriate boxes on the sponsored genetic counseling section of the TRF.

SPECIMEN REQUIREMENTS

Whole Blood

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube), minimum 1 ml for small infants.

Saliva

Oragene™ or GeneFiX™ Saliva Collection kit used according to manufacturer instructions. DNA from saliva specimens is invariably contaminated with microbial and food DNA, which can impact specimen quality and may result in delayed testing and/or the need for a second specimen.

OCD-100 Buccal Swab

OCD-100 Buccal Swab used according to manufacturer instructions.

Specimen collection kits: Buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.