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Multicenter Study
. 2023 Dec;38(12):2241-2248.
doi: 10.1002/mds.29617. Epub 2023 Sep 26.

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Alessio Di Fonzo  1   2 , Marco Percetti  1   3   4 , Edoardo Monfrini  1   2 , Ilaria Palmieri  5 , Alberto Albanese  6 , Micol Avenali  5   7 , Anna Bartoletti-Stella  8   9 , Fabio Blandini  10 , Gloria Brescia  10 , Giovanna Calandra-Buonaura  9   11 , Rosa Campopiano  12 , Sabina Capellari  9   11 , Isabel Colangelo  13 , Giacomo Pietro Comi  1   2 , Giada Cuconato  14 , Rosangela Ferese  12 , Caterina Galandra  5   14 , Stefano Gambardella  15 , Barbara Garavaglia  13 , Andrea Gaudio  16 , Emiliano Giardina  17   18 , Federica Invernizzi  13 , Paola Mandich  16   19 , Rossana Mineri  6 , Celeste Panteghini  13 , Chiara Reale  13 , Lucia Trevisan  16 , Stefania Zampatti  17 , Pietro Cortelli  9   11 , Enza Maria Valente  5   14 ; PARKNET study group
Collaborators, Affiliations
Free article
Multicenter Study

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Alessio Di Fonzo et al. Mov Disord. 2023 Dec.
Free article

Abstract

Background and objective: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD 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.

Methods: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification 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 age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic.

Results: In 186 of 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 of 186 (10%) patients, with 5 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.

Conclusions: 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 counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: EOPD; Parkinson's disease; gene panel; next-generation sequencing; variant classification.

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