Objective: Establish an authoritative central curation for causative genes and variants for Parkinson’s disease (PD)

Background: The urgency to establish central curation for causative genes for PD stems from recent advancements in the field towards precision medicine. There are at least 6 clinical trials targeting biological pathways of PD genes, e.g., LRRK2 inhibitors; glucocerebrosidase chaperones; GBA gene therapy; alpha-synuclein antisense oligonucleotides. These trials often use genetic screening as inclusion criteria. However, no PD-related gene has undergone systematic curation as recognized by ClinGen – an FDA recognized resource that uses strictly defined criteria to establish the clinical relevance of genes and variants.

Method: To address these gaps, we formed a ClinGen recognized, Parkinson´s disease gene curation expert panel (PD GCEP) that will establish consensus on the genes in which pathogenic variants are causative for PD and atypical parkinsonism.

Results: To reach a consensus on PD genes and variants according to ClinGen criteria, we established the PD GCEP to help determine the validity of genes-disease relationships associated with PD and atypical parkinsonism. The formal foundation of our multidisciplinary and inclusive panel was approved in August 2020. The panel includes 58 leaders from multiple countries (Canada, France, Germany, Italy, UK, and the USA) representing important relevant disciplines that include molecular genetics, PD clinical genetics, and genetic counseling. The overwhelming willingness of panel invitees to participate in this panel signals a broad belief that this work is of immediate value to the field. The panel has established an initial goal of curating a set of PD genes (LRRK2, GBA, PRKN, PINK1, SNCA, PARK7, VPS35) that have a reasonable consensus as to causality. PD GCEP curations can be found here: https://search.clinicalgenome.org/kb/affiliate/10079

Conclusion: With the curation of several established genes completed (e.g., LRRK2) and additional genes ongoing, we have provided the first set of PD genes that contribute towards adult-onset neurodegenerative disease to ClinGen.  Due to the emergence of clinical trials for GBA and LRRK2, it is now imperative to develop a field-wide consensus via the ClinGen variant pathogenicity framework about the relevance of variants that are clearly associated with PD to help guide precision medicine trials and inform FDA decision-making.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-and-variant-curation-of-parkinsons-disease-genes-by-an-authoritative-expert-panel/