TY - JOUR
T1 - Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies
AU - Savarese, Marco
AU - Johari, Mridul
AU - Johnson, Katherine
AU - Arumilli, Meharji
AU - Torella, Annalaura
AU - Töpf, Ana
AU - Rubegni, Anna
AU - Kuhn, Marius
AU - Giugliano, Teresa
AU - Gläser, Dieter
AU - Fattori, Fabiana
AU - Thompson, Rachel
AU - Penttilä, Sini
AU - Lehtinen, Sara
AU - Gibertini, Sara
AU - Ruggieri, Alessandra
AU - Mora, Marina
AU - Maver, Ales
AU - Peterlin, Borut
AU - Mankodi, Ami
AU - Lochmüller, Hanns
AU - Santorelli, Filippo Maria
AU - Schoser, Benedikt
AU - Fajkusová, Lenka
AU - Straub, Volker
AU - Nigro, Vincenzo
AU - Hackman, Peter
AU - Udd, Bjarne
N1 - Funding Information:
This study was supported by Association Fran-caise contre les Myopathies (M.S.), Orion foundation (M.S.), Magnus Ehrnrooth Foundation (M.S.), Päivikki ja Sakari Sohlbergin Säätiö (M.S.), Jane and Aatos Erkko Foundation (P.H.), Medicinska Understödsföreningen Liv och Hälsa rf (P.H.), Folkhälsan Research Foundation (B.U.), Erkko Foundation (B.U.), Juselius Foundation (B.U.), Finnish Academy (B.U.), Telethon Italy (V.N.) and Telethon-UILDM (Unione Italiana Lotta alla Dis-trofia Muscolare) (V.N.). The MYO-SEQ project was supported by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J Brazzo Foundation, LGMD2D Foundation, Kurt+Peter Foundation, Muscular Dystrophy UK and Coalition to Cure Calpain 3. The HTS work in inherited myopathies in Pisa Lab is supported by Regione Toscana FAS SALUTE 2014 (CUP 4042.16092014.066000060 to FMS). H.L. and R.T. are supported by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement Nos. 305444 (RD-Connect). AM is supported by Intramural Research Program at National Institute of Neurological Disorders and Stroke.
Publisher Copyright:
© 2020 - IOS Press and the authors. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
AB - BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.
KW - cardiomyopathies
KW - clinical interpretation
KW - data sharing
KW - skeletal muscle disorders
KW - Titin
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U2 - 10.3233/JND-190423
DO - 10.3233/JND-190423
M3 - Article
C2 - 32039858
AN - SCOPUS:85082147832
VL - 7
SP - 153
EP - 166
JO - Journal of Neuromuscular Diseases
JF - Journal of Neuromuscular Diseases
SN - 2214-3599
IS - 2
ER -