Genotype-phenotype correlations in recessive titinopathies

Marco Savarese^{1

2}, Anna Vihola^{3

4

5}, Emily C Oates⁶, Rita Barresi⁷, Chiara Fiorillo⁸, Giorgio Tasca⁹, Manu Jokela¹⁰, Anna Sarkozy¹¹, Sushan Luo¹², Jordi Díaz-Manera^{13

14

15}, Christoffer Ehrstedt^{16

17}, Ricardo Rojas-García^{13

14}, Amets Sáenz¹⁸, Nuria Muelas^{14

19}, Fortunato Lonardo²⁰, Heidi Fodstad²¹, Talha Qureshi^{3

4}, Mridul Johari^{3

4}, Salla Välipakka^{3

4}, Helena Luque^{3

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 Illa^{13

14}, Juan J Vílchez^{14

19}, Cedric Julien²⁷, Ana Ferreiro^{27

28}, Alessandro Malandrini²⁹, Chong-Bo Zhao¹², Olivera Casar-Borota³⁰, Mark Davis³¹, Francesco Muntoni^{11

32}, Peter Hackman^{3

4}, Bjarne Udd^{3

4

33}

Affiliations

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.

PMID: 32778822
DOI: 10.1038/s41436-020-0914-2

Free article

Genotype-phenotype correlations in recessive titinopathies

Marco Savarese et al. Genet Med. 2020 Dec.

Free article

. 2020 Dec;22(12):2029-2040.

doi: 10.1038/s41436-020-0914-2. Epub 2020 Aug 11.

Authors

Affiliations

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.

PMID: 32778822
DOI: 10.1038/s41436-020-0914-2

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.

Keywords: arthrogryposis; cardiomyopathy; congenital myopathy; skeletal muscle disorders; titin.

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References

1. Bang ML, Centner T, Fornoff F, et al. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. 2001;89:1065–1072. - DOI
1. Linke WA, Kulke M, Li H, et al. PEVK domain of titin: an entropic spring with actin-binding properties. J Struct Biol. 2002;137:194–205. - DOI
1. Savarese M, Jonson PH, Huovinen S, et al. The complexity of titin splicing pattern in human adult skeletal muscles. Skelet Muscle. 2018;8:11. - DOI
1. Bryen SJ, Ewans LJ, Pinner J, et al. Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. Hum Mutat. 2020;41:403–411. - DOI
1. Savarese M, Sarparanta J, Vihola A, Udd B, Hackman P. Increasing role of titin mutations in neuromuscular disorders. J Neuromuscul Dis. 2016;3:293–308. - DOI

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Genotype-phenotype correlations in recessive titinopathies

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Genotype-phenotype correlations in recessive titinopathies

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