A Titin Truncating Variant Causing a Dominant Myopathy With Cardiac Involvement in a Large Family: The Exception That Proves the Rule.

Autor:	Claeys KG; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Savarese M; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Jonson PH; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Goosens V; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Topf A; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Vihola A; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Straub V; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland., Udd B; From the Department of Neurology (K.G.C.), University Hospitals Leuven; Department of Neurosciences (K.G.C.), Laboratory for Muscle Diseases and Neuropathies, KU Leuven, and Leuven Brain Institute (LBI), Belgium; Folkhälsan Research Center and Medicum (M.S., P.H.J., A.V., B.U.), University of Helsinki, Finland; Department of Radiology (V.G.), University Hospitals Leuven, Belgium; John Walton Muscular Dystrophy Research Centre (A.T., V.S.), Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Neuromuscular Research Center (B.U.), Department of Neurology, Tampere University and University Hospital; and Department of Neurology (B.U.), Vaasa Central Hospital, Finland.
Jazyk:	angličtina
Zdroj:	Neurology. Genetics [Neurol Genet] 2024 Aug 12; Vol. 10 (5), pp. e200185. Date of Electronic Publication: 2024 Aug 12 (Print Publication: 2024).
DOI:	10.1212/NXG.0000000000200185
Abstrakt:	Background: Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders. Objective: To determine whether a single heterozygous nonsense variant in TTN can be responsible for the observed dominant myopathy in a large family. Methods: In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically. Results: All affected family members showed a similar clinical phenotype with a combination of cardiac and skeletal muscle involvement. Muscle imaging data revealed titin-compatible hallmarks. Genetic analysis revealed in all affected patients a nonsense TTN variant c.70051C>T p.(Arg23351*), in exon 327. RNA sequencing confirmed the lack of complete nonsense-mediated decay, and protein studies convincingly revealed expression of a shortened titin fragment of the expected size. Discussion: We conclude that a single heterozygous nonsense variant in titin occasionally can cause a dominant myopathy as shown in this large family. Therefore, monoallelic titin truncating variants should be considered as possible disease-causing variants in unsolved patients with a dominant myopathy. However, large segregation studies, muscle imaging, and RNA and protein assays are needed to support the clinical and genetic interpretation. Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu