Objective: We aimed to investigate the genetic architecture of Parkinson’s disease (PD) in the island-based Cretan population by identifying pathogenic/likely pathogenic variants (ACMG criteria), in genes linked to PD and to explore potential genotype-phenotype associations.

Background: The Cretan PD Cohort (CPDC) is a growing database from Crete, whose inhabitants bear characteristics of an isolated population. Despite small sample sizes, such populations are valuable for studying complex diseases like PD, offering greater genetic and environmental homogeneity and enhancing the detection of recessive alleles.

Method: PD patients from the CPDC were recruited between 2020-2023. Genetic analysis included SNP genotyping (NeuroBooster array) for all patients, whole-exome sequencing and PCR-based detection of specific GBA1 variants in selected cases.

Results: 315 PD patients (59.7% men; age at diagnosis 62.0±11.2 years) were enrolled. Early-onset PD (<50 years) was observed in 21.3% of patients, while 31.4% had a positive family history with no significant association between the two. In total, 27 pathogenic/likely pathogenic variants were identified, including 25 heterozygous carriers of nine autosomal-dominant variants [GBA1 (n=17); LRRK2 (n=5); SNCA (n=1); GCH1 (n=2)], two homozygous carriers of two autosomal-recessive variants [(PINK1 (n=1); FIG4 (n=1)], and 34 heterozygous carriers of 16 autosomal-recessive variants [PNPLA6 (n=9); ATP13A2 (n=7); POLG (n=6); PRKN (n=5); PINK1 (n=4); SPG7 (n=2); PARK7 (n=1); GCH1 (n=1)]. While most variants have been implicated in PD pathogenesis, four had no prior association with parkinsonism and five lacked available reports. Patients homozygous for autosomal-recessive variants or heterozygous for autosomal-dominant variants had a significantly lower age at diagnosis (p=0.013), while the latter were more likely to have a positive family history (p=0.0371). No pathogenic/likely pathogenic variants were detected in about three-quarters of patients with early-onset PD and/or positive family history, suggesting non-genetic factors, cryptic mutations, or variants of poorly defined pathogenicity.

Conclusion: In a large sample from Crete, 8.6% of cases were attributed to genetic PD, while an additional 10.8% were heterozygous carriers of recessive pathogenic/likely pathogenic variants. Although these figures fall at the higher end of the genetic PD spectrum, many variants remain unidentified and warrant further investigation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-analysis-of-parkinsons-disease-in-crete/