Marco Savarese1,2, Anna Vihola3,4,5, Emily C Oates6, Rita Barresi7, Chiara Fiorillo8, Giorgio Tasca9, Manu Jokela10, Anna Sarkozy11, Sushan Luo12, Jordi Díaz-Manera13,14,15, Christoffer Ehrstedt16,17, Ricardo Rojas-García13,14, Amets Sáenz18, Nuria Muelas14,19, Fortunato Lonardo20, Heidi Fodstad21, Talha Qureshi3,4, Mridul Johari3,4, Salla Välipakka3,4, Helena Luque3,4, Philippe Petiot22, Adolfo López de Munain18, Marika Pane23, Eugenio Mercuri23, Annalaura Torella24, Vincenzo Nigro24, Guja Astrea25, Filippo Maria Santorelli25, Claudio Bruno8, Thierry Kuntzer26, Isabel Illa13,14, Juan J Vílchez14,19, Cedric Julien27, Ana Ferreiro27,28, Alessandro Malandrini29, Chong-Bo Zhao12, Olivera Casar-Borota30, Mark Davis31, Francesco Muntoni11,32, Peter Hackman3,4, Bjarne Udd3,4,33. 1. Folkhälsan Research Center, Helsinki, Finland. marco.savarese@helsinki.fi. 2. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland. marco.savarese@helsinki.fi. 3. Folkhälsan Research Center, Helsinki, Finland. 4. Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland. 5. Neuromuscular Research Center, Fimlab Laboratories, Tampere University and University Hospital, Tampere, Finland. 6. School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, Australia. 7. Rare Diseases Advisory Group Service for Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital, and The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Translational and Clinical Research Institute, University of Newcastle, Newcastle upon Tyne, UK. 8. Paediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. 9. Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 10. Neuromuscular Research Center, Tampere University Hospital and Tampere University, Tampere, Finland. 11. Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK. 12. Department of Neurology, Huashan Hospital Fudan University, Shanghai, China. 13. Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain. 14. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. 15. John Walton Muscular Dystrophy Research Center, University of Newcastle, Newcastle, UK. 16. Department of Women and Childrens Health, Section for Paediatrics, Uppsala University, Uppsala, Sweden. 17. Uppsala University Childrens Hospital, Uppsala, Sweden. 18. Group of Neuromuscular Diseases, Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain. 19. Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari I Politècnic La Fe, Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain. 20. UOSD Genetica Medica, AO Rummo, Benevento, Italy. 21. Department of Laboratory Medicine and Pathology, Division of Genetic Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland. 22. Hospices Civils de Lyon, Explorations Fonctionnelles Neurologiques, Hôpital de la Croix Rousse, Lyon, France. 23. Pediatric Neurology and Nemo Clinical Centre, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Roma, Italy. 24. Medical Genetics, Department of Biochemistry, Biophysics and General Pathology University of Campania 'Luigi Vanvitelli' Naples Italy, Caserta, Italy. 25. Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy. 26. Department of Neurosciences, Nerve-Muscle Unit, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland. 27. Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), Institut de Myologie, GH Pitié-Salpêtrière, Paris, France. 28. Basic and Translational Myology Lab, UMR8251 BFA, Université de Paris/CNRS, Paris, France. 29. Neurology and Neurometabolic Unit, Department of Medicine, Surgery, and Neurosciences, University of Siena, Siena, Italy. 30. Department of Clinical Pathology, Uppsala University Hospital, Uppsala, Sweden. 31. Department of Diagnostic Genomics, Department of Health, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia. 32. NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK. 33. Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
Abstract
PURPOSE: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. METHODS: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). RESULTS: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). CONCLUSION: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
PURPOSE: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. METHODS: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). RESULTS: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). CONCLUSION: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
Authors: Marco Savarese; Jaakko Sarparanta; Anna Vihola; Per Harald Jonson; Mridul Johari; Salla Rusanen; Peter Hackman; Bjarne Udd Journal: Acta Myol Date: 2020-12-01