Objective: This study aims to determine the mutation spectrum of Mendelian Parkinson’s disease (PD) genes and clinical features of mutation carriers within a cohort of early-onset and familial Chinese PD samples collected at our hospital over the past decade.

Background: Currently, more than 20 genes, supported by diverse genetic evidence, are suggested to be associated with monogenic PD. The mutation spectrum of PD differs among different populations.

Method: A cohort of 600 PD probands was assembled, consisting of 107 probands from families with parental consanguinity (consanguineous PD), 30 from families with non-consanguineous autosomal recessive PD (nonconsanguineous ARPD), 64 from families with autosomal dominant PD (ADPD), and 399 with sporadic early-onset PD (sEOPD). A comprehensive genetic analysis was conducted using a combination of methods, including homozygosity mapping, cDNA sequencing, MLPA assay, and next-generation sequencing.

Results: A total of 57 probands (57/600, 9.5%) were identified with rare pathogenic/likely pathogenic variants in PD-related genes. The molecular diagnosis rate correlated significantly with age at onset (AAO): 56.25% (27/48), 14.97% (22/147), 1.54% (5/325), and 3.75% (3/80) for AAO ≤30, 31-40, 41-50, and >50 years, respectively. Notably, ARPD, encompassing both consanguineous PD and non-consanguineous ARPD, exhibited a significantly higher diagnosis rate (26.28%) compared to ADPD and sEOPD (4.69% and 4.51%). LRRK2 p.N1437S and PLA2G6 deep intron mutations were identified for the first time in Chinese PD cases. PRKN biallelic mutations were the most prevalent (n = 34, 5.67%), followed by LRRK2 (n = 7, 1.17%), PLA2G6 (n = 5, 0.83%), PINK1 (n = 4, 0.67%), SNCA (n = 3, 0.5%), DJ-1 (n = 2, 0.33%), SYNJ1 (n = 1, 0.17%), and VPS13C (n = 1, 0.17%). Patients with mutations in PRKN, PINK1, PLA2G6, and DJ-1 exhibited a significantly lower AAO compared to non-carriers, while the AAO in patients with LRRK2 and SNCA mutations did not differ significantly from that of non-carriers.

Conclusion: Our study contributes additional insights into the genetic spectrum of early-onset and familial PD in Chinese, which may hold significance for the development of genetic scanning strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-mendelian-mutations-in-a-large-chinese-early-onset-and-familial-parkinsons-disease/