Familial Transthyretin Amyloidosis (TTR) Sequencing

Preferred test for genetic confirmation of ATTR amyloidosis

  • Useful for confirming a diagnosis when a pathogenic sequence variant has been identified in a family member
  • A copy of the family member’s lab report documenting the familial variant is REQUIRED.

Familial transthyretin (ATTR) amyloidosis is a genetic disorder that is caused by pathogenic variants in the TTR gene and results in amyloid deposits consisting of mutated TTR.  It is characterized by progressive peripheral sensorimotor or autonomic neuropathy, with nonneuropathic changes including cardiomyopathy, nephropathy, vitreous opacities, and central nervous system amyloidosis.   ATTR amyloidosis is inherited in an autosomal dominant manner and accounts for the majority of hereditary amyloidosis cases. Genetic testing is indicated to confirm a clinical diagnosis of ATTR amyloidosis by distinguishing it from other types of amyloidosis, cardiomyopathy, or neuropathy and as a predictive test for individuals at risk for ATTR amyloidosis.  

Disease Overview

Associated Phenotypes

TTR Amyloidosis Phenotypes
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
  • CNS symptoms
  • Glaucoma
  • Nephropathy
  • Vitreous opacities

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

CNS, central nervous system

Source: Sekijima, 2001 

Familial Euthyroid Hyperthyroxinemia

  • Asymptomatic increase in total serum thyroxine concentration 
  • Caused by benign TTR variants

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 

Epidemiology

  • 1/100,000 in individuals of northern European descent in the U.S. 
  • Up to 1/538 in individuals of Portuguese descent 
  • The frequency of p.Val142Ile, associated with late-onset cardiac amyloidosis, is 3.0-3.9% in African Americans 

Genetics

Etiology

Pathogenic TTR germline variants

Penetrance

Incomplete, but varies greatly depending on :

  • Ethnic groups
  • Geographic regions
  • Variants

Inheritance

Autosomal dominant 

Variants

There are two primary founder variants, c.148G>A (p.Val50Met) and c.424G>A (p.Val142Ile). Gain-of-function sequence variants account for >99% of pathogenic variants detected, though missense, nonsense, and splice-site variants may also be causative for disease.  ATTR amyloidosis has a poor phenotype-genotype correlation.

Screening Issues

Presymptomatic genetic testing is useful to diagnose ATTR 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 Description

Clinical Sensitivity

Approximately 99% for ATTR amyloidosis

Analytical Sensitivity

Variant Class Analytical Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) Analytical Specificity (NPA) (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a diagnosis of hereditary amyloidosis.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the TTR coding regions and intron-exon boundaries
    • Regulatory region and deep intronic variants
    • Noncoding transcripts
    • Large exonic deletions/duplications/inversions
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes or repetitive/homologous regions

Results

Result Variant(s) Detected Clinical Significance

Positive

One or more pathogenic TTR variant(s) detected

Confirms a clinical diagnosis of ATTR amyloidosis

Negative

No pathogenic TTR variants detected

Decreases likelihood of, but does not exclude, a diagnosis of ATTR amyloidosis

Inconclusive

Variant of uncertain significance detected

Diagnosis of  ATTR amyloidosis is uncertain

References