Category: Parkinson's Disease: Genetics
Objective: To investigate the genetic causes of Malaysian early-onset Parkinson’s disease (EOPD) patients with whole genome sequencing (WGS).
Background: EOPD (age of diagnosis ≤50 years) comprises ~10% of all PD patients worldwide. Monogenic factors are postulated to play a major role in EOPD but the majority (~80%) remain genetically unsolved.
Method: We recruited 161 index Malaysian EOPD patients. Next-generation sequencing-based CENTOGENE PD gene panel and multiplex ligation-dependent probe amplification (MLPA) identified monogenic causes in 35 patients (21.7%)1. The remaining unsolved patients underwent short-read WGS under the Global Parkinson’s Genetics Program (GP2)2. Currently, data for 65 of those are available. Single nucleotide variant (SNV), copy number variation (CNV) and repeat expansion in rarer PD and neurological disorder (ND)-related genes were analyzed using standard pipelines as described2.
Results: Via Gauchian pipeline, we found two carriers of the GBA1 RecNciI variant and a copy number loss, that were missed by gene panel sequencing. Twenty-three patients carried potentially disease-causing variants in PD and ND genes more rarely related to PD: one patient with two heterozygous variants of uncertain significance (VUS) in VPS13C [p.C2588F; p.C2588S], one patient with a heterozygous, pathogenic TWNK [p.Ala293ProfsTer33] variant and one patient with homozygous EPM2A exon 5 deletion. Another 20 patients (30.8%) carried single heterozygous VUS in AFG3L2, DCTN1, GCH1, MAPT, OPA1, PDGFB, POLG, SPG7 and SQSTM1. There were no carriers of pathogenic repeat expansions in ND-related genes, but 3Chinese patients (4.6%; 2 females and 1 male) harbored heterozygous FMR1 gray zone (GZ) expansions (42-49 repeats)3.
Conclusion: Other than the two GBA1 carriers, the genetic causes of our EOPD cohort with negative prescreening by gene panel and MLPA remained largely inconclusive after short-read WGS for known PD and ND-related genes. One caveat is our relatively high rate of VUS, partly due to the unknown background population frequencies of detected variants. Segregation studies, long-read sequencing, and collaborative, genome-wide analyses will be required to facilitate the interpretation of these and other variants from underrepresented cohorts. Lastly, our finding adds to the existing literature3 of a potential link between FMR1 GZ expansions and PD, which warrants further investigation in a larger case-control cohort.
References: 1. Tay YW, Tan AH, Lim JL, Lohmann K, Ibrahim KA, Abdul Aziz Z, et al. Genetic study of early-onset Parkinson’s disease in the Malaysian population. Parkinsonism Relat Disord. 2023;111:105399.
2. Lange LM, Avenali M, Ellis M, Illarionova A, Keller Sarmiento IJ, Tan AH, et al. Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2). NPJ Parkinsons Dis. 2023;9(1):100.
3. Hall DA, Nag S, Ouyang B, Bennett DA, Liu Y, Ali A, et al. Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death. Mov Disord. 2020;35(8):1448-56.
To cite this abstract in AMA style:
YW. Tay, TS. Toh, JW. Hor, JL. Lim, KA. Ibrahim, AS. Mawardi, TT. Lim, I. Looi, YK. Chia, JCE. Ooi, WC. Law, J. Wong, YH. Lau, PC. Teh, TL. Ong, WK. Cheah, LC. Lit, KA. Muthusamy, L. Lange, KL. Lohmann, ZH. Fang, CK. Klein, AA. Ahmad-Annuar, SY. Lim, AH. Tan. Whole Genome Sequencing of an Early-onset Malaysian Parkinson’s Disease Cohort [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/whole-genome-sequencing-of-an-early-onset-malaysian-parkinsons-disease-cohort/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/whole-genome-sequencing-of-an-early-onset-malaysian-parkinsons-disease-cohort/