Factsheet TTR HEREDITARY AMYLOIDOSIS

Clinical features CENTOGENE ID 542 Gene(s) name (OMIM, HGNC) TTR Gene OMIM 176300 Transthyretin gene (TTR) are associated with an autosomal dominant disease leading to clinical symptoms through Disease OMIM 105210 deposits, especially in the , but also in the lungs, blood vessels, Gene location 18q12.1 and kidneys. Hereditary transthyretin amyloidosis must be suspected in adults with slowly progressive sensorimotor and/or , , conduction block, , anginal pain, INHERITANCE PATTERN congestive and sudden death. Autosomal dominant

The phenotype of Hereditary Transthyretin amyloidosis (ATTR) depends on the specific TTR where some common mutations have been predominantly associated with cardiac involvement. The missense variant DISEASE SYNONYMS V142I is by far the most common cause of cardiac ATTR in African-Americans. Hereditary amyloidosis transthyretin-related; Transthyretin The disease usually begins with sensory neuropathy in the lower extremities amyloidosis; familial Amyloid . with paresthesias and hypesthesias of the feet, or autonomic neuropathy (, constipation alternating with , attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, MATERIAL anhidrosis, and urinary retention or incontinence). Currently, more than 150 different mutations in the gene have been described. MINIMUM MINIMUM EDTA MINIMUM DNA (µg) BLOOD (ml) FILTERCARDS (pcs) Most of the TTR gene mutations that cause transthyretin amyloidosis are thought to alter the structure of transthyretin, impairing its ability to 1 1 1 bind to other transthyretin and altering its normal function. For reasons that are unclear, the transthyretin abnormally begins to form protein deposits. TURNAROUND TIME In elderly people, deposits of amyloid protein cause a condition called senile systemic amyloidosis. People with this condition do not have a Estimated working days upon sample receipt mutation in the TTR gene. FULL GENE FULL GENE SEQUENCING AND SEQUENCING DELETION/DUPLICATION ANALYSIS The most common place for amyloidosis in people with this condition is the heart, causing slowly progressive heart failure. Other sites of 10 20 amyloidosis may include the lungs, blood vessels, and kidneys. It is estimated that 10 to 25 percent of people older than 80 have senile systemic amyloidosis (Connors et al., 2016).

CONTACT AND CUSTOMER SERVICE Phone: +49 (0)381 80 113 - 416 Email: [email protected] Fax: +49 (0)381 80 113 - 401 www.centogene.com Differential diagnosis

A total of 35 amyloidogenic proteins including transthyretin (TTR) have been identified in human amyloidosis, and among the hereditary amyloidosis, familial TTR amyloidosis is the most prevalent. Other amyloidosis to consider in the differential diagnosis of Hereditary Transthyretin (ATTR) amyloidosis are neuropathic amyloidosis and systemic amyloidosis.

Neuropathic amyloidosis includes amyloidosis and Apo AI amyloidosis. Systemic amyloidosis include wild type transthyretin amyloidosis (senile systemic amyloidosis), and Immunoglobulin amyloidosis.

Diagnostic strategy Referral reasons

We offer the following assay selection for diagnosing TTR The following individuals are candidates for this associated hypertrophic : particular gene testing:

• Sequence analysis/mutation scanning of entire coding and • Individuals with a family history of ATTR and presentation flanking intronic regions of the gene with NGS single gene of the most common symptoms sequencing (confirmation of low quality variants and all insertions/deletions by Sanger) • Individuals without a positive family history, but with symptoms resembling this disease • If no mutation is identified, deletion/duplication analysis will be performed using qPCR • Individuals with a negative but suspected family history, in order to perform proper genetic counseling

Test utility

Sequencing and deletion/duplication testing of this gene as well as related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes. Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconceptional options, and allow for appropriate referral for patient support and/or resources.

REFERENCES

• Connors, LH, Sam F, Skinner M, Salinaro F, Sun F, Ruberg FL, Berk JL, Seldin DC. Heart failure resulting from age-related cardiac amyloid disease associated with wildtype transthyretin: a prospective, observational cohort study. Circulation. 2016;133:282-290. • Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363:1881–91. • Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve. 2007;36:411–23. • Sekijima Y. Hereditary Transthyretin Amyloidosis. 2001 Nov 5 [Updated 2018 Dec 20]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®

[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1194. V1.1eng_April2020