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.

Lack of TMEM230 mutations in patients with familial and sporadic Parkinson's disease in a Taiwanese population.

Mutations in transmembrane protein 230 (TMEM230) have recently been reported to be associated with Parkinson's disease (PD) in a North American population. A highly prevalent mutation, c.550_552delTAGinsCCCGGG (p.*184ProGlyext*5) was found in 3.1% of Chinese familial PD patients. However, subsequent studies failed to replicate these findings in different populations. Our objective was to confirm the role of this gene in a large number of PD patients and controls in a Taiwanese population. Among 1,672 participants, we sequenced all coding exons and exon-intron boundary junctions of the TMEM230 gene in 180 probands with familial PD. We also genotyped the potential pathogenic variants identified and the previously reported mutations (p.Arg141Leu, p.Tyr92Cys, p.*184Trpext*5, and p.*184ProGlyext*5) in an additional cohort of 500 patients with sporadic PD, and 992 age and gender-matched neurologically normal control subjects. We did not find any of the previously reported mutations, but we observed one novel missense exonic variant, c.G68A (p.Arg23Gln), in one patient with familial PD, and two patients with sporadic PD in a heterozygous state. However, subsequent analysis of this variant in 992 controls did not find any significant associations between p.Arg23Gln and the risk of PD (0.44% vs. 0.30%, p = 0.22). Our findings suggest that genetic variants of TMEM230 do not play a major role in PD in our Taiwanese population. Further experimental studies are warranted to confirm the pathogenicity of this gene in PD disease process.

Lack of CHCHD2 mutations in Parkinson's disease in a Taiwanese population.

A recent study identified a missense mutation in coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) gene, p.Thr61Ile, in a Japanese multigenerational family with autosomal dominant Parkinson's disease (PD). Subsequent analyses identified several genetic variants in this gene that contributed to increased risk of sporadic PD, making CHCHD2 a novel candidate gene associated with PD. However, independent studies are warranted to confirm the role of CHCHD2 in PD. Among 1433 participated subjects, we sequenced all exons and exon-intron boundaries of CHCHD2 from 137 probands with familial PD and 129 age/sex-matched controls. An additional 586 sporadic PD patients and another 581 independent controls were later screened to validate possible risk substitutions. We found no CHCHD2 mutations, but we observed 5 genetic variants, including p.Pro2Leu (rs142444896), a risk variant for sporadic PD in Japanese populations. However, we did not find any significant associations between p.Pro2Leu (rs142444896) and risk of PD in our study cohort (0.86% vs. 1.20%, p = 0.20). Our data suggest that genetic variants of CHCHD2 do not play a major role in our Taiwanese PD population.

Clinical heterogeneity of LRRK2 p.I2012T mutation.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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, and Tc99mTRODAT-SPECT imaging findings of this index family were similar to idiopathic PD. CONCLUSIONS: 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.

COQ2 p.V393A variant, rs148156462, is not associated with Parkinson's disease in a Taiwanese population.

A recent collaborative study that combined linkage analysis with whole-genome sequencing of family members of multiplex families with multiple system atrophy (MSA) has identified COQ2 gene as a causative gene for MSA. The common variant, c.T1178C (p.V393A, rs148156462), in the COQ2 gene was found to be associated with an increased risk of sporadic MSA. There is overlapping clinical characteristics between MSA and Parkinson's disease (PD), and the pathologic hallmark of both diseases is α-synucleinopathy. We therefore aim to analyze the COQ2 p.V393A variant in a large Taiwanese cohort with PD patients. We genotyped COQ2 p.V393A variant in a total of 1005 participants, comprising 500 patients with PD and 505 age/gender-matched control subjects. The frequency of TC/CC genotype was comparable between PD patients and control subjects (odds ratio: 0.81, 95% confidence interval: 0.42-1.56, p = 0.53). COQ2 p.V393A variant is not a genetic risk factor for PD, suggesting its specificity in disease susceptibility to MSA.

Mutational analysis of SYNJ1 gene (PARK20) in Parkinson's disease in a Taiwanese population.

Whole-exome sequencing recently identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1, PARK20), p.Arg258Gln, in 2 independent families with autosomal recessive young-onset parkinsonism with seizures and cognitive decline. This mutation's role in typical Parkinson's disease (PD) is unclear. We sequenced all coding exons and exon-intron boundaries of SYNJ1 gene in a total of 700 participants: 250 early-onset PD patients, 100 familial PD patients with family history, and 350 age/sex-matched controls from Taiwan. No patients harbored homozygous or compound heterozygous mutations of SYNJ1 gene in our study population. We observed 1 novel missense substitution, p.Ala551Val, in a single heterozygous state in 1 early-onset PD patient. This variant was not observed in controls with total 700 normal alleles. The clinical phenotype of this genetic variant carrier is similar to that seen in idiopathic PD, with motor fluctuation after 11 years of PD diagnosis and comorbidity with dementia after 13 years of motor symptoms. Our results suggest that mutations in SYNJ1 gene do not play a major role in early-onset or familial PD in our population.