Familial Transthyretin Amyloidosis (TTR) Sequencing

Interpretive Data: Background Information for Familial Transthyretin Amyloidosis (TTR) Sequencing:
Characteristics: Familial Transthyretin Amyloidosis  is caused by pathogenic variants of the TTR gene resulting in abnormal amyloid accumulation in various tissues and is generally categorized into three phenotypes:  1) familial amyloid polyneuropathy, a slowly progressive sensorimotor and autonomic neuropathy; 2) familial amyloid cardiomyopathy, a restrictive cardiomyopathy with cardiomegaly, conduction block, angina, congestive heart failure and aortic dissection/dilatation; and 3) leptomeningeal amyloidosis, primarily affecting the CNS, causing dementia, visual impairment, seizures, ataxia, psychosis, hemorrhage, and hydrocephalus. TTR variants can also be associated with benign familial euthyroid hyperthyroxinemia.
Incidence: 1 in 568 individuals from Northern Portugal; 1 in 100,000 individuals of Northern European ancestry.
Inheritance: Autosomal dominant.
Penetrance: Incomplete.
Cause: Pathogenic TTR gene variants.
Clinical Sensitivity: 99 percent for Familial TTR Amyloidosis.
Methodology: Bidirectional sequencing of all coding regions and intron-exon boundaries of the TTR gene.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Regulatory region variants, deep intronic variants and large deletions/duplications in TTR will not be detected.