title: A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population.
abstract: Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.
authors.affiliation: Neurology Clinic, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Stojan
authors.initials: S
authors.lastname: Perić
authors.affiliation: Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.
authors.forename: Jelena Nikodinović
authors.initials: JN
authors.lastname: Glumac
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Töpf
authors.affiliation: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors.forename: Dušanka
authors.initials: D
authors.lastname: Savić-Pavićević
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Lauren
authors.initials: L
authors.lastname: Phillips
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Johnson
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Cassop-Thompson
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Liwen
authors.initials: L
authors.lastname: Xu
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Bertoli
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: MacArthur
authors.affiliation: Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors.forename: Miloš
authors.initials: M
authors.lastname: Brkušanin
authors.affiliation: Department of Pathology, Clinical Hospital Centre Zemun, Belgrade, Serbia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Milenković
authors.affiliation: Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.
authors.forename: Vedrana Milić
authors.initials: VM
authors.lastname: Rašić
authors.affiliation: Centre for Radiology and Magnetic Resonance Imaging, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Banko
authors.affiliation: Centre for Radiology and Magnetic Resonance Imaging, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Ružica
authors.initials: R
authors.lastname: Maksimović
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Neurology Clinic, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Vidosava Rakočević
authors.initials: VR
authors.lastname: Stojanović
authors.affiliation: The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D064211:Connectin / Q000235:genetics*; D003402:Creatine Kinase / Q000097:blood; D049310:Distal Myopathies / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D055771:Serbia; D013577:Syndrome
chemical_list: D064211:Connectin; C577285:TTN protein, human; D003402:Creatine Kinase