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

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.

The lack of association between ubiquinol‐cytochrome c reductase core protein I (UQCRC1) variants and Parkinson's disease in an eastern Chinese population

“…Therefore, it can be hypothesized that UQCRC1 variants may play a role in the development of PD. Recently, UQCRC1 was identified as a candidate pathogenic gene for PD 6 . Nevertheless, we did not find an association between sporadic PD and UQCRC1 in our study.…”

“…Ubiquinol‐cytochrome c reductase core protein I (UQCRC1) is a component of the complex III in the respiratory chain complex. Recently, Lin et al used a whole‐exome sequencing and discovered a novel candidate pathogenetic missense variant (c.941A > C p.Y314S) of the UQCRC1 gene in a Taiwanese family with autosomal dominant parkinsonism 6 . To further investigate the association between UQCRC1 and PD in eastern China, we performed a UQCRC1 genetic analysis in a cohort of sporadic PD patients and healthy controls.…”

Association study of DNAJC13, UCHL1, HTRA2, GIGYF2 and EIF4G1 with Parkinson’s disease

“…Since the original description, several studies have reported other genetic variants in Italian cohorts (p.R903K) (Gagliardi et al, 2018) and Taiwanese cohorts (p.G394V and p.R1382H), yet the pathogenicity of these variants has not been confirmed. In addition, other previously described variants did not segregate by disease (p.R1516H and p.L2170W) (Ross et al, 2016), and in cohorts with sparse number of probands with rare variants in DNAJC13 (Gagliardi et al, 2018;Lin et al, 2019). No other study was able to confirm the pathogenicity of the DNAJC13 p.N855S variant.…”

Quality of Life in Newly Diagnosed Patients With Parkin-Related Parkinson's Disease

“…Parkinson's disease (PD), one of the most prevalent progressive neurodegenerative disorders, is characterized by motor dysfunctions such as bradykinesia, tremor and rigidity, as well as varieties of non-motor symptoms (NMSs) (1). Bi-allelic mutations in the Parkin gene are the most common cause of autosomal recessive early-onset PD (EOPD), accounting for 10.1% of patients with disease onset before the years of 40 in the Asian population (2). So far, genotypic and phenotypic characteristics of Parkinrelated PD have been well-demonstrated in the literature.…”