Objective: Aim of the study is to report the frequency of variants of uncertain significance (VUS) in a cohort of patients with early-onset Parkinson’s disease (EOPD) who underwent genetic evaluation.

Background: Despite advancements in genetic testing, a significant proportion of EOPD cases remain genetically unresolved due to the identification of VUS.

Method: In our cohort of Parkinson’s disease (PD) patients, 836 were diagnosed with EOPD of whom 46 underwent genetic evaluation either with whole exome sequencing (WES) or Parkinson gene panel testing.

Results: Based on our analysis of genetic data of a cohort of 46 cases with EOPD, we identified a total of 100 variants, with 73 (73%) categorized as VUS. Among the 46 cases, 38 (82.6%) had at least one VUS mutation with 25 (65.8%) patients exhibiting two or more VUS variants. Specifically, 18 patients had two VUS mutations, 5 had three VUS mutations, 1 had four VUS mutations, and 1 had five VUS mutations. The most common genes that VUS mutations were found in were VPS13C, ATP13A2, ATP7B, FBXO7, PINK1, TENM4, LRRK2, and PLA2G6.

Conclusion: Our findings highlight the substantial prevalence of variants of uncertain significance in EOPD cases, with over 70% of mutations in our cohort falling into this category. Notably, most of the individuals with VUS mutations (more than 65%) harbor two or more VUS mutations which underscores the complexity of genetic factors involved.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frequency-of-variants-of-uncertain-significance-in-a-cohort-of-early-onset-parkinsons-disease-patients/