title: Homozygous truncating mutation in prenatally expressed skeletal isoform of TTN gene results in arthrogryposis multiplex congenita and myopathy without cardiac involvement.
abstract: We report the case of a newborn with arthrogryposis multiplex congenita and severe axial hypotonia without cardiac involvement in which, using a customized targeted next-generation sequencing assay for 64 myopathy-associated genes, we detected a novel homozygous truncating mutation, c.38661_38665del, in exon 197 of the TTN gene that is expressed only in the fetal skeletal isoform. Its pathogenicity is supported by evidence of maternal isodisomy for chromosome 2. Muscle pathology showed fibers with core-like areas devoid of oxidative staining and cytoplasmic bodies. Electron microscopy showed the replacement of the sarcomeric structure with filamentous material. Identification of this mutation expands the phenotypic spectrum of the TTN gene and shows for the first time that a mutation not found in adult TTN isoforms is involved in the development of a neuromuscular disorder. TTN mutations should be considered in all severe congenital myopathies with arthrogryposis without cardiac involvement.
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, Spain; Centro de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: amarmiesse@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Marmiesse
authors.affiliation: Neuropediatric Unit, Complejo Universitario Hospitalario de Albacete, Albacete, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Carrascosa-Romero
authors.affiliation: Neonatology Service, Complejo Universitario Hospitalario de Albacete, Albacete, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Alfaro Ponce
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Nascimento
authors.affiliation: Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ortez
authors.affiliation: Institut de Myologie, UPMC Université, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.
authors.forename: Norma
authors.initials: N
authors.lastname: Romero
authors.affiliation: Progenika Biopharma, A Grifols Company, Derio, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Palacios
authors.affiliation: Centro de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jimenez-Mallebrera
authors.affiliation: Centro de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Pathology Department, Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Gouveia
authors.affiliation: Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, A Coruña, Spain; Centro de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Couce
mesh_terms: D001176:Arthrogryposis / Q000235:genetics*; D064211:Connectin / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D009135:Muscular Diseases / Q000151:congenital / Q000235:genetics*; D009154:Mutation; D020033:Protein Isoforms
chemical_list: D064211:Connectin; D020033:Protein Isoforms; C577285:TTN protein, human
keywords: Arthrogryposis multiplex congenita; Core myopathy; Isodisomy; Prenatally expressed isoform; TTN