This test analyzes the TTR gene associated with familial transthyretin amyloidosis—the most common type of familial amyloid polyneuropathy.
Individuals with clinical symptoms of transthyretin amyloidosis may benefit from diagnostic genetic testing to better understand risks, confirm a diagnosis, or inform management. Asymptomatic individuals within a family with a known pathogenic variant may also benefit, as it may clarify their own personal risk of developing transthyretin amyloidosis or inform medical management.
Transthyretin amyloidosis can also be ordered as part of broader panels to test for cardiomyopathy disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Transthyretin amyloidosis is characterized by amyloidosis, the buildup of abnormal amyloid protein deposits in the body. Transthyretin amyloidosis can present with progressive axonal sensory autonomic and motor neuropathy and infiltrative cardiomyopathy. Additional features may include conduction block, nephropathy, vitreous opacities, or neurological symptoms related to CNS amyloidosis. Transthyretin amyloidosis can also be an acquired condition, due to age-related deposition of TTR, referred to as senile systemic amyloidosis.
The TTR gene is the only gene associated with transthyretin amyloidosis. Sequence analysis identifies >99% of pathogenic variants.
Transthyretin amyloidosis is inherited in an autosomal dominant pattern.
Transthyretin amyloidosis exhibits reduced penetrance, meaning that not everyone who inherits a predisposition to transthyretin amyloidosis will develop the disease. Homozygosity for common TTR pathogenic variants can be associated with earlier age of onset—though not exclusively, as some homozygous individuals remain asymptomatic. The penetrance has been observed to differ by population, with a higher penetrance in Portuguese population, as compared to Swedish and French populations.
Some TTR variants predispose to cardiomyopathy, with or without neuropathy. Other TTR variants are primarily associated with features of neuropathy. Significant clinical variability exists, even within the same family. However, as amyloidosis progresses, affected individuals typically experience more symptoms as amyloid deposits accumulate in more tissues.
The prevalence of transthyretin amyloidosis is population-specific, with certain variants accounting for the majority of transthyretin amyloidosis in populations where it is endemic. The most common pathogenic TTR variant, Val30Met, has the highest frequency in Portuguese, Japanese, and Swedish populations. The Val122Ile variant occurs in approximately 4% of individuals of African American ancestry.
This test may be considered for individuals with:
For links to published management guidelines for cardiology conditions, please refer to our Management guidelines page.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|