Eurasian Journal of Medicine · Published 2026-07-17 · DOI 10.5152/eurasianjmed.2026.251209
Siti Nornazihah Mohd Rosdi, Abdul Aziz Mohamed Yusoff
Background: Chiari malformation type 1 (CM1) is a neurological disorder characterized by cerebellar tonsil herniation. While nuclear DNA has been associated with craniovertebral development, the role of mitochondrial DNA (mtDNA) remains unclear. This study investigated nuclear DNA variants (PAX1, EPAS1, DKK1, GDF6) and mtDNA D-loop mutations in CM1 patients from East Coast Malaysia. Methods: Sixty-eight participants were enrolled, comprising 38 CM1 patients and 30 controls. Genomic DNA from peripheral blood was analyzed by polymerase chain reaction amplification and Sanger sequencing. Associations between genetic variants and clinicopathological parameters (age, sex, tonsillar herniation, syringomyelia) were assessed using chi-square or Fisher’s exact test. Results: Four nuclear DNA variants were identified, comprising a synonymous PAX1 mutation (c.555G>A, p.K185K) and intronic changes in EPAS1 (c.1035-7C>G), DKK1 (c.548-3T>C), and GDF6 (c.406+112T>C), none of which exhibited significant associations with clinicopathological characteristics. In contrast, mtDNA analysis revealed that 50% of CM1 patients (n = 30) harbored D-loop mutations, predominantly T>C or G>A transitions, including 18 novel variants. Mutation frequency was significantly higher in patients with more severe tonsillar herniation (>10 mm) (OR = 28.570; 95% CI: 3.080-250.000; P < .001) and in those with syringomyelia (OR = 7.792; 95% CI: 1.782-34.060; P = .007), while no significant associations were observed with age or sex. Conclusion: Nuclear DNA variants may function as genetic modifiers without significant clinical impact. Conversely, mtDNA D-loop mutations were prevalent and correlated with disease severity, suggesting a contributory role in CM1 pathogenesis and warranting further investigation of mitochondrial genetic factors. Cite this article as: Rosdi SNM, Mohamed Yusoff AA. Nuclear and mitochondrial DNA variants in Chiari malformation type 1: insights from an east coast Malaysian cohort. Eurasian J Med. 2026, 58(4), 1209, doi: 10.5152/eurasianjmed.2026.251209.
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Rosdi, S., Yusoff, A. (2026). Nuclear and Mitochondrial DNA Variants in Chiari Malformation Type 1: Insights from an East Coast Malaysian Cohort. Eurasian Journal of Medicine. https://doi.org/10.5152/eurasianjmed.2026.251209