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Effectiveness and Utility of Genetic Testing in Establishing a Diagnosis of Hereditary Transthyretin Amyloidosis

Publication Details

Journal of Molecular Genetics and Metabolism Reports

September 2025

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Author(s)

Akash Singh¹, John Wyatt², Marie Théaudin³, Chafic Karam⁴, David Kasper⁵, Berthold Streubel⁶, Karen Frascello², Antoine Bondue⁷

Affiliations

¹Alnylam Pharmaceuticals, London SL6 1DA, UK; ²Alnylam Pharmaceuticals, Cambridge, MA 02142, USA; ³Service of Neurology, Neurosciences Department, Lausanne University Hospital (CHUV), University of Lausanne, 1011 Lausanne, Switzerland; ⁴Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA; ⁵ARCHIMED Life Science GmbH (ARCHIMEDlife), 1110 Vienna, Austria; ⁶Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; ⁷Department of Cardiology, Hôpital Universitaire de Bruxelles, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium

Abstract

Background/Objectives:

Hereditary transthyretin amyloidosis (ATTRv) is a progressive and fatal disease with >130 known underlying variants in the TTR gene. We describe the utility of two no-charge genetic testing programs in identifying TTR variants in participants across Europe/Middle East and North America, respectively.

Methods:

Eligible adult participants in GeneAct® and Alnylam Act® had a family history or clinical suspicion of ATTRv. Testing was performed using gene panels for neuropathies or cardiomyopathy, or a single-gene TTR test. Diagnostic yield was defined as one pathogenic/likely pathogenic variant in TTR.

Results:

Overall, 2713 and 89,760 participants were tested in GeneAct® and Alnylam Act®. Genetic diagnosis was established in 95 and 4297 participants, respectively, resulting in a diagnostic yield of 3.5% and 4.8%. V122I (p.V142I) was the most common variant, identified in 34 of these participants in GeneAct® and 3299 in Alnylam Act®. Cardiac and neurologic signs/symptoms were the most common manifestations across both programs, as reflected in the specialties ordering tests in Alnylam Act® (cardiology, 29.1%; neurology, 31.5%).

Conclusions:

These data highlight the importance of genetic testing for early identification of ATTRv, especially among patients with cardiac and neuropathy symptoms. Genetic testing has the potential to improve diagnostic timeframes and outcomes in ATTRv.