Journal article
Genotype-phenotype correlations in recessive titinopathies.
- Savarese M Folkhälsan Research Center, Helsinki, Finland. marco.savarese@helsinki.fi.
- Vihola A Folkhälsan Research Center, Helsinki, Finland.
- Oates EC School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, Australia.
- Barresi R 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.
- Fiorillo C Paediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- Tasca G Unità Operativa Complessa di Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
- Jokela M Neuromuscular Research Center, Tampere University Hospital and Tampere University, Tampere, Finland.
- Sarkozy A Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK.
- Luo S Department of Neurology, Huashan Hospital Fudan University, Shanghai, China.
- Díaz-Manera J Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
- Ehrstedt C Department of Women and Childrens Health, Section for Paediatrics, Uppsala University, Uppsala, Sweden.
- Rojas-García R Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
- Sáenz A Group of Neuromuscular Diseases, Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.
- Muelas N Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
- Lonardo F UOSD Genetica Medica, AO Rummo, Benevento, Italy.
- Fodstad H Department of Laboratory Medicine and Pathology, Division of Genetic Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Qureshi T Folkhälsan Research Center, Helsinki, Finland.
- Johari M Folkhälsan Research Center, Helsinki, Finland.
- Välipakka S Folkhälsan Research Center, Helsinki, Finland.
- Luque H Folkhälsan Research Center, Helsinki, Finland.
- Petiot P Hospices Civils de Lyon, Explorations Fonctionnelles Neurologiques, Hôpital de la Croix Rousse, Lyon, France.
- de Munain AL Group of Neuromuscular Diseases, Neurosciences Area, Biodonostia Health Research Institute, San Sebastián, Spain.
- Pane M Pediatric Neurology and Nemo Clinical Centre, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Roma, Italy.
- Mercuri E Pediatric Neurology and Nemo Clinical Centre, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Roma, Italy.
- Torella A Medical Genetics, Department of Biochemistry, Biophysics and General Pathology University of Campania 'Luigi Vanvitelli' Naples Italy, Caserta, Italy.
- Nigro V Medical Genetics, Department of Biochemistry, Biophysics and General Pathology University of Campania 'Luigi Vanvitelli' Naples Italy, Caserta, Italy.
- Astrea G Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
- Santorelli FM Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
- Bruno C Paediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- Kuntzer T Department of Neurosciences, Nerve-Muscle Unit, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland.
- Illa I Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu I Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain.
- Vílchez JJ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
- Julien C Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.
- Ferreiro A Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile-de-France (APHP), Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.
- Malandrini A Neurology and Neurometabolic Unit, Department of Medicine, Surgery, and Neurosciences, University of Siena, Siena, Italy.
- Zhao CB Department of Neurology, Huashan Hospital Fudan University, Shanghai, China.
- Casar-Borota O Department of Clinical Pathology, Uppsala University Hospital, Uppsala, Sweden.
- Davis M Department of Diagnostic Genomics, Department of Health, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
- Muntoni F Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK.
- Hackman P Folkhälsan Research Center, Helsinki, Finland.
- Udd B Folkhälsan Research Center, Helsinki, Finland.
- 2020-08-12
Published in:
- Genetics in medicine : official journal of the American College of Medical Genetics. - 2020
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1038/s41436-020-0914-2
- PMID 32778822
- Persistent URL
- https://sonar.ch/global/documents/24976
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