title: Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations.
abstract: The autosomal recessive spinocerebellar ataxias are an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. SYNE1 was originally discovered in 2007 as the causal gene underlying autosomal recessive spinocerebellar ataxia 1, a disease clinically thought to manifest with mainly pure cerebellar ataxia. Since the original report SYNE1 mutations have also been identified in families with motor neuronopathy and arthrogryposis but few families have been screened as the gene is very large at 146 exons in length. We screened 196 recessive and sporadic ataxia patients for mutations in SYNE1 using next generation sequencing in order to assess its frequency and extend the clinicogenetic spectrum. We identified four novel truncating mutations spread throughout the SYNE1 gene from three families living in London that originated from England, Turkey and Sri Lanka. The phenotype was mainly pure cerebellar ataxia in two families, cognitive decline was present in all three families, axonal neuropathy in one family and marked spasticity in the Turkish family, with a range of disease severities. Searching for genotype-phenotype correlations in the SYNE1 gene, defects located near the 3' prime end of the gene are more frequently associated with motor neuron or neuromuscular involvement so far. Our data indicate SYNE1 mutations are not an uncommon cause of recessive ataxia with or without additional clinical features in patients from various ethnicities. The use of next generation sequencing allows the rapid analysis of large genes and will likely reveal more SYNE1 associated cases and further expand genotype-phenotype correlations.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Centre for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wiethoff
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hersheson
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Conceicao
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. h.houlden@ucl.ac.uk.|Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. h.houlden@ucl.ac.uk.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000328:Adult; D000368:Aged; D002524:Cerebellar Ataxia / Q000150:complications / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index; D013188:Sri Lanka; D014421:Turkey; D006113:United Kingdom
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C415465:SYNE1 protein, human
keywords: Clinical severity; Gene; Genotype–phenotype; Mutation; SYNE1; Spinocerebellar ataxia