Objective: Our study aimed to identify the genetic determinants and their prevalence in an Italian cohort of Parkinson’s disease (PD) patients.

Background: Advances in genetics have expanded the known spectrum of PD-related genes. The new techniques have broadened the access to genetic analysis, allowing for rapid and simultaneous sequencing of many disease-associated genes, although unraveling a high number of variants, with interpretation difficulties and inconsistencies.

Method: PD patients with family history of PD (>=1 affected relative), early-onset (<=55 years^[1]), and/or atypical phenotype underwent genetic analysis through an NGS panel containing 45 known-PD-causative genes, coupled with MLPA when needed. Variants were interpreted according to the ACMG^[2] criteria, and reports were categorized as positive (>=1 variant, with definite genetic diagnosis), inconclusive (>=1 variant, insufficient for genetic diagnosis), or negative (no variants reported).

Heterozygous pathogenic/likely pathogenic variants in dominant genes and biallelic pathogenic/likely pathogenic variants in recessive genes were considered positive. GBA1 variants were considered pathogenic^[3] and classified based on the risk of PD-development^[3]. Inconclusive reports underwent reassessment: heterozygous pathogenic variants in recessive genes and variants of unknown significance (VUS) with genotype-phenotype mismatch were considered negative; VUS not otherwise interpretable were clarified through family segregation studies.

Results: We recruited 197 patients. 74 (37.6%) reports revealed >=1 variant. Of the inconclusive 39 (19.8%) reports, after reinterpretation, 1 (0.5%) was considered positive, while 22 (11.2%) were interpreted as negative. Eventually, positive reports were 36 (18.3%), and inconclusive 16 (8.1%). The most common diagnoses included GBA1 (23, 11.7%), LRRK2 (5, 2.5%), PRKN (4, 2.0%), PINK1 (1, 0.5%) FBXO7 (1, 0.5%). The gene with the most reported variants was GBA1 (28, 27.7%), followed in order by PRKN, LRRK2, POLG, PINK1, DNAJC13, and EIF4G1.

Conclusion: Our results contribute to a more in-depth understanding of the genetic spectrum underlying PD in Italian patients and underscore the importance of a standardized and shared approach for the accurate interpretation of genetic findings.

References: 1. Di Fonzo A, Percetti M, Monfrini E, et al. Harmonizing Genetic Testing for Parkinson’s Disease: Results of the PARKNET Multicentric Study. Mov Disord. 2023;38(12):2241-2248. doi:10.1002/mds.29617
2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
3. Parlar SC, Grenn FP, Kim JJ, Baluwendraat C, Gan-Or Z. Classification of GBA1 Variants in Parkinson’s Disease: The GBA1-PD Browser. Mov Disord. 2023;38(3):489-495. doi:10.1002/mds.29314

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-genetic-landscape-of-parkinsons-disease-in-an-italian-cohort-and-the-need-for-a-standardized-approach/