How many do we miss? - Evaluation of age at onset and family history as selection criteria for genetic testing in Parkinson’s disease

Importance Current recommendations for genetic testing in Parkinson’s disease (PD) prioritize groups of patients based on age at onset (AAO) and family history (FH). The increasing importance of identifying genetic PD for personalized counseling and potential gene-specific therapies calls for a data-driven evaluation of these recommendations.

To estimate the diagnostic accuracy, specifically the sensitivity, specificity, and positive predictive value (PPV), of genetic testing in PD based on AAO and FH. Design, Setting, and Participants We analyzed data from six cohorts within four independent datasets: ROPAD, PD GENEration, the MDSGene database, the Global Parkinson’s Genetics Program (GP2), and two German observational studies. These datasets included 25,063 PD participants, of whom 6,295 carried pathogenic or likely pathogenic variants. ROPAD and PD GENEration, both prospective genetic screening studies, served as representative real-world cohorts. Main Outcome(s) and Measure(s) For each gene, we quantified the proportion of carriers by age bracket and familial vs. sporadic status. Receiver operating characteristic (ROC) curves, and area under the curve (AUC) values with 95% confidence intervals (CIs) were calculated for AAO and FH. PPVs were computed based on sensitivity, specificity, and prevalence.

An AAO threshold of ≤50 identified 32% (ROPAD), 23% (PD GENEration), 63% (MDSGene), and 30% (GP2) of genetic cases. ROC analyses based on AAO alone yielded AUCs of 0.59 (CI: 0.57-0.60, ROPAD), 0.58 (CI: 0.56-0.60, PD GENEration), 0.78 (CI: 0.75-0.80, MDSGene), and 0.54 (CI: 0.52-0.56, GP2), respectively. Combining AAO with FH increased AUCs to 0.60 (CI: 0.59-0.62), 0.60 (CI: 0.58-0.62), 0.83 (CI: 0.81-0.85), and 0.58 (CI: 0.56-0.60). FH improved AUCs for dominant genes such as LRRK2 (e.g., 0.52 to 0.61 in ROPAD) but had minimal or no effect for recessive genes (e.g., PRKN/PINK1: 0.90 to 0.90 in ROPAD).

and Relevance Current selection criteria (AAO ≤50) identify only a minority (23–32%) of variant carriers. Most carriers (68–77%) present with a later AAO and remain undetected. While AAO is moderately predictive in some cohorts, it insufficiently captures late-onset genetic forms, particularly LRRK2-PD and GBA1-PD. The limited incremental value of FH challenges its use as a selection criterion. These findings support revised, data-driven testing strategies to improve detection of genetic PD across all age groups. Question What are the diagnostic accuracy, specifically the sensitivity, specificity, and positive predictive value, of the current age at onset and family history-based selection criteria for genetic testing to identify major gene pathogenic variant carriers among patients with Parkinson’s disease? Findings Performing genetic testing in Parkinson’s disease patients with an early age at onset ≤50 years results in a positive genetic finding in one of four patients; however, this criterion captures only 23–32% of known variant carriers in population-based datasets, underscoring its limited sensitivity and leading to substantial underdiagnosis of genetic Parkinson’s disease. The additional discriminatory value of family history is marginal. Meaning Revised recommendations for broader genetic testing in Parkinson’s disease are warranted. Competing Interest Statement The authors have declared no competing interest. Funding Statement DFG FOR2488 to AW, JT, MK, KL, NB, and CK. AB, JT, and CK would like to acknowledge support from GP2, funded by the Aligning Science Across Parkinson's initiative and implemented by The Michael J. Fox Foundation. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data used in the preparation of this manuscript were obtained from six independent cohorts. 1. GP2 Data: The Global Parkinson's Genetics Program (GP2) database can be accessed via the Terra platform (https://app.terra.bio/#workspaces). For up-to-date information on GP2 data acquisition, access, and policies, visit https://gp2.org/. This project was supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org/). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF). For a complete list of GP2 members, see [url=x-msg://28/doi.org/10.5281/zenodo.7904831]doi.org/10.5281/zenodo.7904831. Prior to submitting patient data to GP2, all contributing centers must receive ethics approval from their local Ethics Committee. The GP2 compliance group must approve all studies and their use of data. 2. PD GENEration data: The study was approved by centralized and site institutional review boards (IRBs), as well as the Scientific Review and Executive Committees of the Parkinson Study Group. 3. ROPAD data: The ROPAD study has been approved by the Ethics Committee (EC) at the Medical Faculty of the University of Rostock (A 2019-0017). 4. MDSGene data: MDS Gene only consists of data that is extracted from published papers. 5. EPIPARK data: The EPIPARK study has been approved by the Ethics Committee of the University of Luebeck. 6. The DeNoPa study received approval from the ethical standards committee on human experimentation (Landesaerztekammer Frankfurt). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Funding sources for study: DFG FOR2488 to AW, JT, MK, KL, NB, and CK. AB, JT, and CK would like to acknowledge support from GP2, funded by the Aligning Science Across Parkinson’s initiative and implemented by The Michael J. Fox Foundation. Data Availability Data used in the preparation of this article were obtained, among others, from the Global Parkinson's Genetics Program (GP2; https://gp2.org). Specifically, we used Tier 2 data from GP2 release 9 (DOI 10.5281/zenodo.14510099). GP2 data are available on AMP PD (https://amp-pd.org). Data were also obtained from ROPAD, PD GENEration, the MDSGene database, and two German observational studies (EPIPARK and DeNoPa). These datasets can be accessed by individual request to the corresponding author. All code generated for this article, and the identifiers for all software programs and packages used, are available on GitHub (https://github.com/GP2code/Genetic_Testing_in_PD) and were given a persistent identifier via Zenodo (DOI: 10.5281/zenodo.17567723).