A clinical and genetic study of early‐onset and familial parkinsonism in taiwan: An integrated approach combining gene dosage analysis and next‐generation sequencing

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.