Familial Transthyretin Amyloidosis (TTR) Sequencing

Familial Transthyretin Amyloidosis (TTR) Sequencing 2014035
Method: Polymerase Chain Reaction/Sequencing

Preferred test for genetic confirmation of familial TTR amyloidosis

Related Test
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known

Familial transthyretin (TTR) amyloidosis is a genetic disorder resulting in amyloid deposits consisting of mutated TTR and characterized by progressive neuropathy.   TTR amyloidosis, along with several genetically related disorders, is caused by pathogenic variants in the TTR gene.  Genetic testing is indicated to confirm a clinical diagnosis of familial TTR amyloidosis, familial euthyroid hyperthyroxinemia, or wild-type amyloid TTR (ATTR) amyloidosis, and as a predictive test for individuals at risk for TTR amyloidosis.  

Disease Overview

Prevalence

  • ~1/100,000 in individuals of northern European descent in the U.S. 
  • Up to 1/568 in Portuguese 

Typical Age of Onset

  • Between 20-50 years in those of Japanese or Portuguese descent 
  • Later age of onset for those with Swedish, French, or British ancestry 

Symptoms

TTR Amyloidosis
Phenotype ATTR Amyloid Neuropathy (Familial Amyloid Polyneuropathy) ATTR Cardiac Amyloidosis (Familial Amyloid Cardiomyopathy) ATTR Leptomeningeal Amyloidosis/Cerebral Amyloid Angiopathy

Symptoms

Early signs

  • Autonomic dysfunction
  • Carpal tunnel
  • Constipation/diarrhea
  • Impotence
  • Sensorimotor polyneuropathy of the legs

Late signs

  • Cardiomyopathy
  • Nephropathy
  • Vitreous opacities
  • Vitreous opacities
  • Glaucoma

Anginal pain

Arrhythmia

Cardiomegaly

Conduction block

Congestive heart failure

Sudden death

Ataxia

Dementia

Hemorrhage (subarachnoid or intracerebral)

Hydrocephalus

Psychosis

Seizures

Spasticity

Transient focal neurologic episodes

Source: Sekijima, 2001 

Familial Euthyroid Hyperthyroxinemia

  • Asymptomatic increase in total serum thyroxine concentration (1-Sekijima)
  • Caused by benign TTR variants

Wild-Type ATTR Amyloidosis (Senile Systemic Amyloidosis)

  • Typically presents in elderly individuals with carpal tunnel syndrome followed by cardiac symptoms 
  • Some develop mild peripheral neuropathy
  • Results from pathogenic deposition of TTR primarily in the heart but no pathogenic TTR variants are present

Genetics

Gene

TTR

Inheritance

Autosomal dominant 

Penetrance

Incomplete, but varies greatly among :

  • Ethnic groups
  • Geographic regions
  • Variants

Variants

  • Gain of function sequence variants account for >99% of pathogenic variants detected 
  • Missense, nonsense, and splice-site variants may be causative for disease 
  • Poor phenotype-genotype correlation

Screening Issues

Presymptomatic genetic testing is useful to diagnose familial TTR amyloidosis because early treatment may delay disease progression. However, it should only be performed for at-risk individuals >18 years of age and should be accompanied by genetic counseling. 

Test Interpretation

Sensitivity

  • Clinical sensitivity: ~99% for familial TTR amyloidosis
  • Analytical sensitivity: 99%

Results

Result Variant(s) Detected Clinical Significance

Positive

One or more pathogenic TTR variant(s) detected

Confirms a clinical diagnosis of familial TTR amyloidosis

Negative

No pathogenic TTR variants detected

Decreases, but does not exclude, risk of familial TTR amyloidosis

Inconclusive

Variant of unknown significance detected

Diagnosis of familial TTR amyloidosis is uncertain

Limitations

  • Not detected:
    • Regulatory region or deep intronic variants
    • Large deletions or duplications
  • Diagnostic errors can occur due to rare sequence variants
References 
  1. Sekijima Y. Hereditary Transthyretin Amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds.. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Dec 2018; Accessed: Aug 2019]
  2. Obici L, Kuks JB, Buades J, Adams D, Suhr OB, Coelho T, Kyriakides T, European Network for TTR-FAP (ATTReuNET). Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016; 29 Suppl 1: S27-35. PubMed

Last Update: September 2019