Objective: The ROPAD study aims to investigate the frequency and spectrum of Parkinson’s disease (PD) genetic causes across a multitude of PD and other movement disorder genes in a multiethnic patient cohort of >12,000 PD patients.

Background: Disease-causing variants in the main PD-related genes (LRRK2, PRKN, VPS35, SNCA, PINK1, PARK7, and GBA) are found in ~10% of PD patients. However, hitherto available estimates of the entire spectrum of pathogenic variants in PD and their frequencies are limited and largely biased. Thus, expanding the number of investigated PD genes and including additional confirmed and candidate genes related to neurological disorders with overlapping clinical features in large and well-phenotyped PD patient cohorts is essential to capture the full spectrum of variants underlying and/or modifying PD

Method: Using a next-generation sequencing panel that targeted 57 genes with an established or possible relevance for PD, we investigated 13,225 individuals, 95% of whom were clinically diagnosed with parkinsonism. The patients were recruited in centers from 16 different countries (Europe ~50%; USA and Canada ~25%).

Results: Our initial analysis focused on the main PD-related genes. Mutations in GBA, LRRK2, PRKN, and SNCA were the underlying cause of disease in 10.6%, 2.9%, 1.0%, and 0.2% of patients, respectively. The remaining three genes (PINK1, PARK7, and VPS35) combined harbored variants that formed the genetic basis of PD in <0.2% of affected individuals. In GBA, the three most prevalent variants were c.1093G>A (p.Glu365Lys), c.1223C>T (p.Thr408Met), and c.1226A>G (p.Asn409Ser) identified in 3.1%, 2.5%, and 2.3% of affected participants, respectively. The most frequently detected LRRK2 variant was c.6055G>A (p.Gly2019Ser), found in 2% of all cases. The highest number of copy-number variations (CNVs) was found in PRKN.  Forty different CNVs were identified in mono or biallelic state and contributed to the molecular diagnosis in >0.7% of cases. ​​​​​​​

Conclusion: Our findings reveal the frequency of different genetic PD forms in the largest multicenter and multiethnic study conducted to date. Notably, apart from providing the most accurate prevalence estimates and the basis for genetic testing and counseling recommendations, the ROPAD study has identified several large cohorts of patients that may participate in future gene-targeted research studies and clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-rostock-international-parkinsons-disease-ropad-study-analysis-of-monogenic-pd-genes/