Expanding the Autosomal Recessive Gene Spectrum of Parkinson's Disease: A Study within the CPD10KGP.

OBJECTIVES Parkinson's disease (PD) has a complex genetic etiology, with autosomal recessive (AR) genes significantly contributing. This study uses next-generation sequencing (NGS) and long-read sequencing data (LRS) in Chinese AR-PD families to uncover novel genes, enhancing our genetic comprehension of PD. METHODS We investigated 162 AR-PD families and 1570 sporadic early-onset PD patients, combining homozygous mapping and whole-exome sequencing (WES) to identify candidates. Using the GenoPriori-WeightSchem approach, we conducted population-based prioritization of candidate genes. We prioritized biallelic loss-of-function variants in the candidate gene pool. LRS dataset were analyzed to investigate genes with structural genomic variants. The identified candidates were further validated in 3947 PD cases from our in-house whole-genome sequencing (WGS) dataset, along with 3100 PD cases derived from the UK Biobank WES dataset. RESULTS Analysis of WES data from 25 core AR-PD families revealed five candidate genes: ROBO1, LMBR1L, RIOX2, INTS2, and H6PD. The GenoPriori-WeightSchem approach highlighted an additional five candidate genes: SORL1, PSD2, BRD9, EPG5, and SH3PXD2A. Focusing on homozygous loss-of-function variants, indicative of severe genetic impact, we identified six genes in AR-PD families: LRPPRC, PPP1R1B, C1RL, LNPK, HSD11B1L, and PPP1R3E. LRS data from 38 families revealed a homozygous structure variant, a 6.3 kb deletion, in the COL24A1 gene. Finally, eight of the identified candidate genes were consistently associated with PD in two independent replication stages. CONCLUSIONS Our study identified eight promising candidate genes using a large sample of AR-PD families, combining NGS and LRS data, which may expand the spectrum of candidate autosomal recessive genes responsible for PD. © 2025 International Parkinson and Movement Disorder Society.