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

ImportanceCurrent recommendations for genetic testing in Parkinsons 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. ObjectiveTo 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 ParticipantsWe analyzed data from six cohorts within four independent datasets: ROPAD, PD GENEration, the MDSGene database, the Global Parkinsons 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. ResultsAn 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). Conclusions and RelevanceCurrent 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. Key Points QuestionWhat 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 Parkinsons disease? FindingsPerforming genetic testing in Parkinsons 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 Parkinsons disease. The additional discriminatory value of family history is marginal. MeaningRevised recommendations for broader genetic testing in Parkinsons disease are warranted.