Genetic study of early-onset Parkinson's disease in the Malaysian population

Tay YW 1 , Tan AH 2 , Lim JL 1 , Lohmann K 3 , Ibrahim KA 4 , Abdul Aziz Z 4 Show all authors , Chin YT 4 , Mawardi AS 5 , Lim TT 6 , Looi I 7 , Chia YK 8 , Ooi JCE 8 , Cheah WK 9 , Dy Closas AMF 2 , Lit LC 10 , Hor JW 2 , Toh TS 2 , Muthusamy KA 11 , Bauer P 12 , Skrahin V 13 , Rolfs A 13 , Klein C 14 , Ahmad-Annuar A 15 , Lim SY 16

Affiliations 

  • 1 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia; Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 3 Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 4 Department of Medicine, Hospital Sultanah Nur Zahirah, Kuala Terengganu, Malaysia
  • 5 Department of Neurology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
  • 6 Island Hospital, Penang, Malaysia
  • 7 Department of Neurology, Seberang Jaya Hospital, Penang, Malaysia
  • 8 Department of Neurology, Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
  • 9 Department of Geriatrics, Taiping Hospital, Taiping, Malaysia
  • 10 Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 11 Division of Neurosurgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 12 Centogene GmbH, Am Strande 7, 18057, Rostock, Germany
  • 13 Centogene GmbH, Am Strande 7, 18057, Rostock, Germany; Arcensus, Goethestrasse 20, 18055, Rostock, Germany
  • 14 Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. Electronic address: christine.klein@neuro.uni-luebeck.de
  • 15 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address: azlina_aa@um.edu.my
  • 16 The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia; Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Electronic address: limshenyang@gmail.com
Parkinsonism Relat Disord, 2023 Jun;111:105399.
PMID: 37209484 DOI: 10.1016/j.parkreldis.2023.105399

Abstract

BACKGROUND: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants.

OBJECTIVES: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort.

METHODS: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA).

RESULTS: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes.

CONCLUSIONS: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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