Journal
JOURNAL OF NEUROMUSCULAR DISEASES
Volume 7, Issue 2, Pages 153-166Publisher
IOS PRESS
DOI: 10.3233/JND-190423
Keywords
Titin; cardiomyopathies; skeletal muscle disorders; clinical interpretation; data sharing
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Funding
- Association Francaise contre les Myopathies
- Orion foundation
- Magnus Ehrnrooth Foundation
- Paivikki ja Sakari Sohlbergin S aatio
- Jane and Aatos Erkko Foundation
- Medicinska Understodsf oreningen Liv och Halsa rf
- Folkhalsan Research Foundation
- Erkko Foundation
- Juselius Foundation
- Finnish Academy
- Telethon Italy
- Telethon-UILDM (Unione Italiana Lotta alla Distrofia Muscolare)
- Sanofi Genzyme
- Ultragenyx, LGMD2I Research Fund
- LGMD2DFoundation
- Kurt+Peter Foundation
- Muscular Dystrophy UK
- Regione Toscana FAS SALUTE [CUP 4042.16092014.066000060]
- European Union [305444]
- Intramural Research Program at National Institute of Neurological Disorders and Stroke
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003131] Funding Source: NIH RePORTER
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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.
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