title: Increasing Role of Titin Mutations in Neuromuscular Disorders.
abstract: The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases.Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN variants. The interpretation of these rare variants of uncertain significance (VOUS) represents a challenge for clinicians and researchers.The main aim of this review is to describe the wide spectrum of muscle diseases caused by TTN mutations so far determined, summarizing the molecular findings as well as the clinical data, and to highlight the importance of joint efforts to respond to the challenges arising from the use of NGS. An international collaboration through a clinical and research consortium and the development of a single accessible database listing variants in the TTN gene, identified by high throughput approaches, may be the key to a better assessment of titinopathies and to systematic genotype- phenotype correlation studies.
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Marco
authors.initials: M
authors.lastname: Savarese
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.|Albert Einstein College of Medicine, Departments of Medicine- Endocrinology and Molecular Pharmacology, Bronx, NY, USA.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Sarparanta
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Vihola
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.|Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.|Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Hackman
mesh_terms: D064211:Connectin / Q000235:genetics*; D049310:Distal Myopathies / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009135:Muscular Diseases / Q000235:genetics; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics; D009468:Neuromuscular Diseases / Q000235:genetics*; D009886:Ophthalmoplegia / Q000235:genetics; D012131:Respiratory Insufficiency / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000172:deficiency / Q000235:genetics
chemical_list: D064211:Connectin; D019837:Ryanodine Receptor Calcium Release Channel; C577285:TTN protein, human
keywords: Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy; Congenital centronuclear myopathy (CNM); Early-onset myopathy with fatal cardiomyopathy (EOMFC); Hereditary myopathy with early respiratory failure (HMERF); Late-onset autosomal dominant tibial muscular dystrophy (TMD); Limb-girdle muscular dystrophy (LGMD); Multi-minicore disease with heart disease (MmDHD); TTN; neuromuscular disorders; titin