Diagnosis; Drug Response; Mutation Confirmation; Pre-symptomatic; Predictive; Prognostic

Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid (CSF) protein that transports holo-retinol-binding protein (RBP; 180250) and thyroxine (T4). It is a homotetrameric protein synthesized mainly in liver, choroid plexus, retinal pigment epithelium, and pancreas. Mutant and wildtype TTR give rise to various forms of amyloid deposition (amyloidosis), … Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid (CSF) protein that transports holo-retinol-binding protein (RBP; 180250) and thyroxine (T4). It is a homotetrameric protein synthesized mainly in liver, choroid plexus, retinal pigment epithelium, and pancreas. Mutant and wildtype TTR give rise to various forms of amyloid deposition (amyloidosis), originally defined pathologically by the formation and aggregation of misfolded proteins which result in extracellular deposits that impair organ function. The clinical syndromes associated with TTR aggregation are familial amyloid polyneuropathy (FAP) and cardiomyopathy (FAP), in which mutant TTR protein aggregates in peripheral and autonomic nerves and heart, respectively; and senile systemic amyloidosis (SSA), a late-onset disorder in which wildtype protein deposits primarily in heart, but also in gut and carpal tunnel View more

Establish or confirm diagnosis

Guidance for management

Predictive risk information for patient and/or family members

Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid (CSF) protein that transports holo-retinol-binding protein (RBP; 180250) and thyroxine (T4). It is a homotetrameric protein synthesized mainly in liver, choroid plexus, retinal pigment epithelium, and pancreas. Mutant and wildtype TTR give rise to various forms of amyloid deposition (amyloidosis), … Transthyretin (TTR) is an evolutionarily conserved serum and cerebrospinal fluid (CSF) protein that transports holo-retinol-binding protein (RBP; 180250) and thyroxine (T4). It is a homotetrameric protein synthesized mainly in liver, choroid plexus, retinal pigment epithelium, and pancreas. Mutant and wildtype TTR give rise to various forms of amyloid deposition (amyloidosis), originally defined pathologically by the formation and aggregation of misfolded proteins which result in extracellular deposits that impair organ function. The clinical syndromes associated with TTR aggregation are familial amyloid polyneuropathy (FAP) and cardiomyopathy (FAP), in which mutant TTR protein aggregates in peripheral and autonomic nerves and heart, respectively; and senile systemic amyloidosis (SSA), a late-onset disorder in which wildtype protein deposits primarily in heart, but also in gut and carpal tunnel View more

All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; … All coding exons and 20 bp of flanking intronic sequence are enriched using an LHSC custom targeted hybridization protocol (Roche Nimblegen), followed by high throughput sequencing (Illumina). Sequence variants and copy number changes are assessed and interpreted using clinically validated algorithms and commercial software (SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual). All exons have >1000x mean read depth coverage, with a minimum 200x coverage at a single nucleotide resolution. This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis. All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request. View more

Mutations identified are repeated in an independent assay using either Sanger sequence or MLP

Tests performed
Entire test performed in-house

This assay meets the sensitivity and specificity of combined Sanger sequencing and MLPA copy number analysis, >99%

Is proficiency testing performed for this test? Help
Yes

Method used for proficiency testing: Help
Inter-Laboratory

PT Provider: Help
internal surveys provided periodically

Software used to interpret novel variations Help
SoftGenetics: Nextgene, Geneticist Assistant, Mutation Surveyor; and Alamut Visual

Laboratory's policy on reporting novel variations Help
All variants interpreted as either ACMG category 1, 2, or 3 (pathogenic, likely pathogenic, VUS; PMID: 25741868) are confirmed using Sanger sequencing, MLPA, or other assays. ACMG category 4 and 5 variants (likely benign, benign) are not reported, but are available upon request.