TTR Gene Sequencing for Transthyretin Amyloidosis

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Gene: TTR at 18q11.2-q12.1

Methodology: Bi-directional DNA sequencing of 3 coding exons and splice sites.

Clinical Sensitivity: TTR variants have been detected in > 99% of patients with a clinical diagnosis.

Sample Requirements

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Amyloidosis is a name given to conditions characterized by accumulation of amyloid (proteinaceous deposits) in various tissues. In transthyretin (TTR) amyloidosis, the most common hereditary form of amyloidosis, the amyloid material is TTR. TTR binds plasma thyroxine and, under certain physiological conditions, also binds plasma retinol binding protein to prevent its excretion by the kidneys. TTR is produced primarily by the liver but also by the choroid plexus and the retina. TTR amyloidosis usually presents in the third or fourth decade, but age of onset and clinical features can vary depending on which tissue is affected by the accumulation of TTR. The disease has a high prevalence in certain ethnic groups such as African Americans.

The most common presentation of TTR is neuropathic which typically manifests as autonomic or sensory motor impairment. Autonomic manifestations include orthostatic hypotension, gastrointestinal abnormalities, carpal tunnel syndrome, inability to sweat, nephropathy, and urinary retention or incontinence. Sensory neuropathy typically begins in the lower extremities with paresthesia (pins and needles sensation) and motor neuropathy eventually ensues within a few years. TTR amyloidosis can result in central nervous system manifestations such as hydrocephalus, dementia, psychosis, seizures, visual impairment and ataxia.

Cardiac involvement in TTR is frequent and most often takes the form of restrictive cardiomyopathy. The enlarged appearance of the interventricular septum and left ventricular muscle reflects the deposition of TTR in these structures rather than true hypertrophy. The symmetrical pattern of enlargement and histological appearance help differentiate this condition from other forms of hypertrophic cardiomyopathy. Additional cardiac symptoms can include arrhythmias, congestive heart failure and sudden death.

Variants in TTR are a primary cause of transthyretin amyloidosis and sequencing of TTR has over 99% sensitivity to detect such varients. Molecular testing for TTR amyloidosis is more sensitive, more specific, and less invasive than tissue biopsy and serum chemical analysis used to confirm the diagnosis.


Familial Amyloid Cardiomyopathy, Familial Amyloid Polyneuropathy Type I (Portuguese-Swedish-Japanese Type), Familial Amyloid Polyneuropathy Type II (Indiana/Swiss or Maryland/German Type), Leptomeningeal Amyloidosis, Familial Oculoleptomeningeal Amyloidosis (FOLMA), Dysprealbunemic Euthyroid Hyperthyroxinemia, Dysprealbunemic Hyperthyroxinemia, Dystransthyretinemic Hyperthyroxinemia, Amyloid Polyneuropathy, Senile Systemic Amyloidosis.

Gene Protein OMIM# Locus
TTR TRANSTHYRETIN 176300 18q11.2-q12.1


  • High prevalence of TTR variants in Portugal, Sweden, and Japan
  • V30M is the most common variant worldwide
    • Frequency of about 1 in 538 in northern Portugal
    • Lower frequency of 1 in 100,000 in American Caucasians
  • V122I variant is frequent in the United States
    • Approximately 4% of African Americans are carriers
    • 5.0% of West Africans are carriers
    • Frequency in American Caucasians and Hispanics is 0.44% and 0.0%, respectively
    • Results in an atypical form of TTR amyloidosis in which cardiac involvement is the predominant feature with no appreciable neuropathy
  • Protective TTR variants exist
Inheritance Pattern
  • Autosomal dominant
  • The presence of a pathogenic variant in one copy of TTR is sufficient to cause TTR amyloidosis.
  • First-degree relatives of an affected individual with an identified pathogenic variant have a 50% (or 1 in 2) chance of inheriting the same variant.
  • Approximately 1/3 of TTR amyloidosis cases are familial and 2/3 are the result of a de novo (new) variant.
    • Incomplete penetrance and variable expressivity exists
  • Age and race may influence these factors
Test Indications
  • Individuals with a clinical diagnosis of TTR amyloidosis
  • Individuals with cardiac amyloidosis as demonstrated by progressive cardiomyopathy (in particular, symmetrical hypertrophy of the interventricular septum and left ventricular wall)
  • Individuals with autonomic neuropathy and/or sensory motor neuropathy
  • Individuals with CNS amyloidosis (may include lepto- or oculoleptomeningeal amyloidosis)
  • Familial carpal tunnel syndrome (testing in sporadic otherwise unexplained carpal tunnel syndrome could also be considered)
  • Family members of an individual with a TTR variant
Test Outcomes
  • The detection of one pathogenic variant in TTR confirms a diagnosis of TTR amyloidosis.
  • A negative test virtually excludes the disease of TTR amyloidosis but other forms of amyloidosis should be considered.


Bi-directional sequence analysis of 4 exons and splice sites of TTR. This test does not detect variants in other non-coding regions, large deletions encompassing one or more exons, or gene rearrangements.

Analytical and Clinical Sensitivity

This assay is greater than 99.9% accurate in detecting variants in the sequence analyzed. According to published data, TTR variants have been detected in over 99% of patients with a clinical diagnosis of TTR amyloidosis.



Benson MD (2001) Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Diseases, 8 ed. Vol 4. McGraw-Hill, New York, pp 5345-78.

Benson MD and Uemichi T (1996) Transthyretin amyloidosis. Amyloid:Int J Exp Clin Invest 3:44-56.

Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN (1997) Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466-73.

Mrner, S, Hellman, U, Suhr, OB, Kazzam, E & Waldenstrm, A (2005) Amyloid heart disease mimicking hypertrophic cardiomyopathy. Journal of Internal Medicine 258 (3), 225-230.

Sekijima, Y., Yoshida, K., Tokuda, T., Ikeda, S. Transthyretin Amyloidosis. GeneReviews ( Accessed 9/11/06.

If you have any questions, please call the Laboratory for Molecular Medicine at 617-768-8500 or email us at