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Neurology and Therapy
Published in: Neurology and Therapy 4/2022

Open Access 06-08-2022 | Amyloidosis | Original Research

Three Newly Recognized Likely Pathogenic Gene Variants Associated with Hereditary Transthyretin Amyloidosis

Authors: Jignesh K. Patel, Andrew M. Rosen, Adam Chamberlin, Benjamin Feldmann, Christian Antolik, Heather Zimmermann, Tami Johnston, Arvind Narayana

Published in: Neurology and Therapy | Issue 4/2022

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Abstract

Introduction

Hereditary transthyretin amyloidosis (ATTRv [variant]) is a clinically heterogeneous, progressively debilitating, fatal disease resulting from the deposition of insoluble amyloid fibrils in various organs and tissues. Early diagnosis of ATTRv can be facilitated with genetic testing; however, such testing of the TTR gene identifies variants of uncertain significance (VUS) in a minority of cases, a small percentage of which have the potential to be pathogenic. The Akcea/Ambry VUS Initiative is dedicated to gathering molecular, clinical, and inheritance data for each TTR VUS identified by genetic testing programs to reclassify TTR variants to a clinically actionable status (e.g., variant likely pathogenic [VLP]) where appropriate.

Methods

Classification criteria used here, based on recommendations from the American College of Medical Genetics and Genomics, are stringent and comprehensive, requiring distinct lines of evidence supporting pathogenesis.

Results

Three TTR variants have been reclassified from VUS to VLP, including c.194C>T (p.A65V), c.172G>C (p.D58H), and c.239C>T (p.T80I). In each case, the totality of genetic, structural, and clinical evidence provided strong support for pathogenicity.

Conclusions

Based on several lines of evidence, three TTR VUS were reclassified as VLP, resulting in a high likelihood of disease diagnosis for those and subsequent patients as well as at-risk family members.
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Metadata
Title
Three Newly Recognized Likely Pathogenic Gene Variants Associated with Hereditary Transthyretin Amyloidosis
Authors
Jignesh K. Patel
Andrew M. Rosen
Adam Chamberlin
Benjamin Feldmann
Christian Antolik
Heather Zimmermann
Tami Johnston
Arvind Narayana
Publication date
06-08-2022
Publisher
Springer Healthcare
Keyword
Amyloidosis
Published in
Neurology and Therapy / Issue 4/2022
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI
https://doi.org/10.1007/s40120-022-00385-1

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