The mutation spectrum of Parkinson‐disease‐related genes in early‐onset Parkinson's disease in ethnic Chinese

Abstract Background and purpose Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD‐related genes and determine the mutational spectrum of early‐onset PD in ethnic Chinese. Methods In this study, whole‐exome sequencing and/or gene dosage analysis were performed in 704 early‐onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty‐six PD‐related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. Results Eighty‐two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD‐related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi‐allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA , p.G284R in PRKN and p.P53Afs*38 in CHCHD2 , occur exclusively in Asians. The putative damaging variants from GBA , PRKN , DJ1 , PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein‐truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late‐onset PD ( n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. Conclusions Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.