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DISCOVERY: a study examining the prevalence of transthyretin mutations in subjects suspected of having cardiac amyloidosis


Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of either immunoglobulin light-chain (AL) or transthyretin (ATTR) fibrils. Two forms of ATTR CA cause life-threatening cardiomyopathy: an inherited form arising from misfolding of mutated ATTR (familial amyloid cardiomyopathy [FAC]) and a sporadic form caused by wild-type ATTR (senile systemic amyloidosis [SSA]). More than half of over 100 reported ATTR mutations are associated with FAC. The most common mutation in the US is Val122Ile found in 3-4% of African Americans (AA). FAC can be difficult to recognize clinically and is likely under diagnosed. The DISCOVERY study aims to determine the prevalence of TTR mutations and FAC diagnosis in a cohort of patients (pts) with clinical features suggestive of CA.


This is a prospective, multi-center study in adults with two or more of the following eligibility criteria: heart failure signs and symptoms, intraventricular septal thickness (IVS) of >12 mm, LV diastolic dysfunction, low voltage ECG, or history of carpal tunnel disease (CTD). DNA from blood samples is used for sequencing of the TTR gene coding regions by a central lab. Assessments in pts with TTR mutations include cardiac biomarkers, echocardiogram and optional abdominal fat pat aspiration and 6-minute walk test. Descriptive statistics will be utilized.


As of May 2015, 146 pts have been enrolled. At baseline, the mean (Std) age of pts is 64 (13) yrs, 61% are men and 66% are AA. A total of 14 (10%) pts had a Val122Ile mutation and 1 pt had a novel mutation Arg103His. The Gly6Ser polymorphism was found in 8 (5%) pts. The Val122Ile cohort consisted of 40% males with a mean (StD) age of 66 (16). Heart failure signs and symptoms and IVS > 12 mm was reported in 71% and 79% of Val122IIle pts respectively. The majority of pts had NYHA class II (56%) and III (22%) heart failure, 21% had low voltage ECGs and 14% had CTD.


These preliminary data suggest that approximately 10% of pts with clinical and/or radiologic findings suggestive of cardiac amyloidosis have a pathogenic TTR mutation which could potentially lead to a diagnosis of FAC. Additional data on clinical features and tissue diagnosis of FAC in these pts will be presented.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Akinboboye, O., Ananthasubramaniam, K., Malik, A. et al. DISCOVERY: a study examining the prevalence of transthyretin mutations in subjects suspected of having cardiac amyloidosis. Orphanet J Rare Dis 10 (Suppl 1), O8 (2015).

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