Objective: This study aimed to assess the mutational spectrum and genetic contribution of DAGLB in Parkinson’s disease (PD) at both the individual and population levels.

Background: Genetic factors play an important role in PD pathogenesis. Our previous study identified biallelic DAGLB variants have been linked to early-onset parkinsonism.

Method: We evaluated rare DAGLB variation using whole-exome sequencing(WES) and whole-genome sequencing(WGS) data in 7,421 unrelated PD cases and 9,903 controls from the Parkinson’s Disease&Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC), with a focus on single-nucleotide variants(SNVs), insertions/deletions(indels), and copy-number variants(CNVs). Gene-based burden analyses were performed for rare variants using SKAT-O. We further screened for biallelic DAGLB variants based on both SNVs/indels and CNVs and characterized the clinical features of variant carriers to explore genotype–phenotype correlations.

Results: In the merged WES/WGS dataset, we identified 211 unique DAGLB variants with MAF <1%. Based on integrated SNV/indel and CNV analyses, we identified four novel homozygousDAGLB variants, including two splice-site variants (c.802-1G>A andc.678+4A>G), one missense variant (c.56T>A,p.V19D), and one deletion CNV (chr7:6432246–6444799del). All identified SNVs/indels and CNVs were validated and RT-PCR demonstrated that the two splice-site variants caused aberrant splicing: c.802-1G>A caused exon 6 skipping whereas c.678+4A>G caused exon 4 skipping, both predicted to disrupt the reading frame. At the population level, gene-based analyses revealed only nominal associations, mainly driven by ultra-rare nonsynonymous and damaging missense variants in the internal 30× WGS cohort and meta-analysis, whereas no significant signal was observed in the WES or 10× WGS cohorts. Genotype–phenotype analysis showed that DAGLB-associated parkinsonism is characterized by early onset, levodopa responsiveness, frequent motor complications, prominent non-motor manifestations, and abnormal 11C-CFT PET findings indicative of nigrostriatal dopaminergic dysfunction.

Conclusion: Our findings support biallelic DAGLB variants as a rare autosomal-recessive cause of early-onset PD, provide the first comprehensive characterization of the DAGLB variant spectrum in a large Chinese population, and expand the recognized genetic and clinical spectrum of DAGLB-associated parkinsonism.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-daglb-variants-in-chinese-patients-with-early-onset-parkinsons-disease/