Objective: We aimed to investigate the frequency of EOPD and PRKN mutations in our diverse Malaysian indigenous populations, who are extremely under-represented in PD genetics research.

Background: Early-onset Parkinson’s disease (EOPD), occurring before age 50, affects ~10% of PD cases. Genetic factors play important roles in the pathogenesis of EOPD, however, studies in South-East Asians remain limited. PRKN mutations are the commonest cause, accounting for ~15% of EOPD.

Method: Consecutive PD patients from various indigenous populations (Bajau, Bugis, Bisaya, Dusun, Kadazan, Murut, Rungus and Suluk) and matched unaffected controls were recruited from Queen Elizabeth Hospital, Sabah. Clinical data including age at onset (AaO) and family history were collected. PRKN copy number variations, point mutations and deletion breakpoint were evaluated using multiplex ligation-dependent probe amplification, polymerase chain reaction and Sanger sequencing.

Results: A total of 104 patients were recruited, of whom 56 (53.8%) were EOPD (mean AaO:37.9±8.9 years, 4 with juvenile-onset <21 years) while 48 had late-onset PD (AaO:61.9±6.9 years). Of 91 index cases, 16 (17.6%) had a family history of PD and 8 (8.8%) reported parental consanguinity. 62.2% of EOPD index cases (28/45) were found to have pathogenic PRKN mutations (19 patients with homozygous exon 3 deletion; 7 with compound heterozygous exon 2 and 3 deletions; 2 with other mutations). A shared deletion breakpoint was discovered in patients with homozygous exon 3 deletion suggesting a possible founder effect in these populations. Heterozygous carrier rates for PRKN exon 2 and exon 3 deletion in controls were 2.0% (1/49) and 8.2% (4/49), respectively.

Conclusion: We found a very high prevalence of EOPD and PRKN mutations (particularly exon 3 deletion) in this first PD genetics cohort study of indigenous South-East Asians. Further studies on the unique genetics of this cohort can potentially provide novel insights with global impact on understanding of the genetic architecture of PD.

This work has previously been presented as a poster presentation locally at the 30th Annual Scientific Meeting of the Malaysian Society of Neurosciences (MSN 2022) on 1^st October 2022, but has not been published.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/very-high-frequency-of-early-onset-parkinsons-disease-with-homozygous-prkn-exon-3-deletion-amongst-indigenous-populations-in-sabah-malaysia/