A clinical and genetic study of early-onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next-generation sequencing
Journal
Movement Disorders
Journal Volume
34
Journal Issue
4
Pages
506-515
Date Issued
2019
Author(s)
Abstract
Background: Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD-causative genes in a Taiwanese PD cohort. Methods: A total of 571 participants including 324 patients with early-onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next-generation sequencing panel containing 40 known PD-causative genes, repeat-primed polymerase chain reaction, and whole-exome sequencing analysis. Results: Thirty of the 324 patients with early-onset parkinsonism (9.3%) were found to carry mutations in Parkin, PINK1, or PLA2G6 or had increased trinucleotide repeats in SCA8. Twenty-nine of 109 probands with autosomal-recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin, PINK1, GBA, or HTRA2. The genetic causes for the 138 probands with an autosomal-dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2, VPS35, MAPT, GBA, DNAJC13, C9orf72, SCA3, or SCA17. A novel missense mutation in the UQCRC1 gene was found in a family with autosomal-dominant inheritance parkinsonism via whole-exome sequencing analysis. Conclusions: Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD-causing mutations. ? 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. ? 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
SDGs
Other Subjects
ataxin 3; core protein; cytochrome c oxidase; dnajc13 protein; fbxo7 protein; gba protein; gigyf2 protein; guanine nucleotide exchange C9orf72; leucine rich repeat kinase 2; levodopa; mapt protein; parkin; pink1 protein; pla2g6 protein; protein; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); sca17 protein; sca8 protein; serine proteinase Omi; succinate dehydrogenase (ubiquinone); synj1 protein; technetium 99m; ubiquinol cytochrome c reductase; ubiquinol cytochrome c reductase core protein I; unclassified drug; vps35 protein; parkin; protein kinase; PTEN-induced putative kinase; ubiquitin protein ligase; adult; amyotrophic lateral sclerosis; Article; ataxic gait; autosomal dominant inheritance; autosomal recessive inheritance; cerebellar ataxia; cohort analysis; consensus sequence; dyskinesia; dystonia; exon; familial disease; fasciculation; female; frontotemporal dementia; gene deletion; gene dosage; gene frequency; genetic analysis; genotype; heterozygote; homozygote; human; human cell; limb weakness; major clinical study; male; middle aged; missense mutation; mitochondrial respiration; motoneuron; multiplex ligation dependent probe amplification; muscle atrophy; mutation rate; nerve conduction; neuropsychological test; next generation sequencing; nuclear magnetic resonance imaging; onset age; Parkinson disease; parkinsonism; pedigree; phenotype; polymerase chain reaction; polyneuropathy; priority journal; psychosis; respiratory chain; Sanger sequencing; sensorimotor neuropathy; SH-SY5Y cell line; Taiwan; treatment response; trinucleotide repeat; whole exome sequencing; aged; genetic predisposition; genetics; high throughput sequencing; onset age; parkinsonism; Adult; Age of Onset; Aged; Female; Gene Dosage; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation, Missense; Parkinsonian Disorders; Protein Kinases; Taiwan; Ubiquitin-Protein Ligases
Type
journal article