Objective: To determine the genetic and demographic patterns of juvenile-onset (JOPD, <20 years), young-onset (YOPD, 20-40 years), and early onset (EOPD, 40-50 years) Parkinson’s disease (PD) in India.

Background: GOPI-YOPD is a prospective multicenter, collaborative study to analyze clinical and genetic patterns of JOPD, YOPD, and EOPD.

Method: Genetic data of 609 samples from a cohort of 668 (Whole Genome Genotyping = 572, Whole Exome Sequencing =519; Whole Genome Sequencing=90) were analyzed. Rare and known pathogenic and risk SNVs/InDels and CNVs in primary PD genes (11), risk PD genes (12), and additional PD genes (40) were analyzed.

Results: A total of 668 subjects (M:F 455:213, mean age at onset of 38.7±8.1 years, mean duration: 8±6 years), whose clinical features have been described by Kukkle etal were analyzed. Genetic analysis revealed significant pathogenic variants in 8.2% of cases (n=50/609), of which 50% (n=25) had SNVs/Indels, 42% (n=21) had copy number deletion in PRKN gene and 6% (n=4) had both. The variants were primarily detected in autosomal recessive PD genes PRKN (n=28, 54.9%), PLA2G6 (n=6, 11.8%), PINK1 (n=4, 7.8%), VPS13C (n=2, 3.9%), ATP13A2 (n=1,1.9%) and SYNJ1 (n=1, 1.9%) and some in autosomal dominant genes – CHCHD2 (n=3, 5.9%), MAPT (n=2, 3.92%). Few additional pathogenic variants were also identified in GCH1 (n=1, 1.9%), PRRT (n=1, 1.9%), and WDR45 (n=1,1.9%). Rare variants less than ≤ 0.001% in the gnomAD database GBA (n=59, 9.7%) and LRRK2 (n= 25, 4.1%) were detected, of whom 9 variants (10.7%) have been previously reported with PD. Overall, the diagnostic yield is found to be high in JOPD (47.62%), followed by YOPD (10%) and EOPD (4%). We also generated PD polygenic risk scores (PRS) using SARGAM genotyping array data. PRS revealed that the PD cases with no prioritized pathogenic/likely pathogenic variants have significantly (p-value < 0.001) higher PD PRS as compared to control population and PD with prioritized pathogenic/likely pathogenic variants.

Conclusion: This large cohort shows differing genetic patterns in JOPD, YOPD, and EOPD cases. PRKN gene is the commonest pathogenetic variant and has large pathogenetic deletions. In addition to pathogenic mutations, a high percentage of VUS indicates untapped genetic understanding. The PRS carries diagnostic utility for possible regular use.

References: Kukkle PL, Goyal V, Geetha TS, Mridula KR, Kumar H, Borgohain R, Mukherjee A, Wadia PM, Yadav R, Desai S, Kumar N, Gupta R, Biswas A, Pal PK, Muthane U, Das SK, Quinn N, Ramprasad VL; Parkinson Research Alliance of India (PRAI). Clinical Study of 668 Indian Subjects with Juvenile, Young, and Early Onset Parkinson’s Disease. Can J Neurol Sci. 2022 Jan;49(1):93-101. doi: 10.1017/cjn.2021.40.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetics-of-parkinsons-in-india-young-onset-parkinsons-disease-gopi-yopd-genetics-of-juvenile-young-and-early-onset-parkinsons-disease/