title: Clinical heterogeneity of LRRK2 p.I2012T mutation.
abstract: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). However, only few cases carrying LRRK2 mutations have been reported in Taiwanese PD patients.
  
  
  
  We used targeted next generation sequencing (NGS), covering 24 candidate genes involved in neurodegenerative disorders, to analyze 40 probands with familial PD, and 10 patients with mixed neurodegenerative disorders. Sanger sequencing of the identified mutation in the first set of the study was performed in additional 270 PD patients, including 139 familial PD and 131 early-onset PD (onset age less than 50 years old), and 300 age/gender matched control subjects.
  
  
  
  We found a missense variant, p.I2012T, in the LRRK2 gene in one sporadic patient having early-onset frontotemporal dementia with parkinsonism and dystonia. Sanger sequencing this substitution in additional 270 PD patients in the second set of the study revealed two additional variant carriers: one having autosomal-dominant familial PD, and one with sporadic PD. The p.I2012T substitution was absent in 300 normal control subjects. Analyzing family members of the proband with p.I2012T revealed co-segregation of the variant and parkinsonism. Clinical presentations, levodopa responses, andTc99mTRODAT-SPECT imaging findings of this index family were similar to idiopathic PD.
  
  
  
  Our results revealed clinical heterogeneity of the LRRK2 p.I2012T substitution, and demonstrated the use of targeted NGS for genetic diagnosis in multiplex families with PD or mixed neurodegenerative disorders.
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Neurology, Landseed Hospital, Ping-jen City, Tao-Yuan County, Taiwan.
authors.forename: Tian-Sin
authors.initials: TS
authors.lastname: Fan
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
authors.affiliation: Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ta-Fu
authors.initials: TF
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Huei-Ying
authors.initials: HY
authors.lastname: Li
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yin-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Meng-Ling
authors.initials: ML
authors.lastname: Chen
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Hwei
authors.initials: CH
authors.lastname: Tai
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Hang-I
authors.initials: HI
authors.lastname: Lin
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: chlin@ntu.edu.tw.
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Lin
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: Frontotemporal dementia; I2012T; LRRK2; Next generation sequencing; Parkinson disease