title: A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations.
abstract: OBJECTIVE
  α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown.
  
  
  OBJECTIVE
  To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications.
  
  
  METHODS
  We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level.
  
  
  METHODS
  We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role.
  
  
  RESULTS
  We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively.
  
  
  CONCLUSIONS
  These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom2The Queen Square Brain Bank, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Aoife P
authors.initials: AP
authors.lastname: Kiely
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.affiliation: Department of Neurology, Frenchay Hospital, Bristol, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giffin
authors.affiliation: Department of Neuropathology, Frenchay Hospital, Bristol, United Kingdom.
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Hehir
authors.affiliation: Biomedical Research Centre, UCL, London, United Kingdom7Education Unit, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Khadija
authors.initials: K
authors.lastname: Rantell
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Amelie
authors.initials: A
authors.lastname: Pandraud
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom8Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Dena G
authors.initials: DG
authors.lastname: Hernandez
authors.affiliation: Department of Academic Hematology, Royal Free Campus, UCL, London, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nacheva
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom2The Queen Square Brain Bank, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Kailash P
authors.initials: KP
authors.lastname: Bhatia
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Niall
authors.initials: N
authors.lastname: Quinn
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom2The Queen Square Brain Bank, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom11MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D017668:Age of Onset; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018628:Gene Dosage; D020440:Gene Duplication / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D019683:Penetrance; D012307:Risk Factors; D012720:Severity of Illness Index; D012737:Sex Factors; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein