Category: Parkinson's Disease: Genetics
Objective: To harmonize the interpretation of genetic testing in Parkinson’s disease (PD) across the PARKNET network, as well as to provide a comprehensive assessment of the genetic basis of early-onset PD (EOPD) in Italy.
Background: EOPD commonly recognizes a genetic basis, thus EOPD patients are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far.
Method: We retrospectively collected data from 648 EOPD patients (age-at-onset, AO≤55y) who underwent NGS of a minimal shared panel of 15 PD-related genes as well as PD-MLPA in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report and final interpretation (positive/negative/inconclusive). Patients were further stratified based on AO≤40y (vEOPD, n=157). All variants were re-classified according to the latest ACMG criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic.
Results: In 186/648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18/186 (10%) patients, with five shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive.
Conclusion: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counselling.
To cite this abstract in AMA style:M. Percetti, E. Monfrini, I. Palmieri, A. Albanese, M. Avenali, A. Bartoletti-Stella, F. Blandini, G. Brescia, G. Calandra-Buonaura, R. Campopiano, S. Capellari, I. Colangelo, G. Comi, G. Cuconato, R. Ferese, C. Galandra, S. Gambardella, B. Garavaglia, A. Gaudio, E. Giardina, F. Invernizzi, P. Mandich, R. Mineri, C. Panteghini, C. Reale, L. Trevisan, S. Zampatti, P. Cortelli, E. Valente, A. Di Fonzo. Harmonizing genetic testing for early-onset Parkinson’s disease: results of the PARKNET multicentric study [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/harmonizing-genetic-testing-for-early-onset-parkinsons-disease-results-of-the-parknet-multicentric-study/. Accessed September 25, 2023.
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