Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 30.
doi: 10.1002/mds.70027. Online ahead of print.

Compound Heterozygous Structural Variants in Cases with Unsolved PRKN-Associated Parkinson's Disease

Agata Fant  1 , Sara Trova  1 , Edoardo Monfrini  2   3 , Gaia Treves  1 , Francesco Musacchia  1   4 , Fabio Landuzzi  5 , Paola Mandich  6 , Antonio Amoroso  1 , Remo Sanges  4   7 , Luca Pandolfini  4 , Francesco Cavallieri  8 , Franco Valzania  9 , Valentina Fioravanti  10 , Giulia Di Rauso  8   9 , Gloria Brescia  10 , Enza Maria Valente  11   12 , Valeria Tiranti  13 , Luigi Michele Romito  14 , Chiara Reale  13 , Barbara Garavaglia  13 , Antonio Emanuele Elia  14 , Andrea Cavalli  5   15   16 , Alessio Di Fonzo  3 , Manuela Vecchi  1 , Stefano Gustincich  1   4
Affiliations

Compound Heterozygous Structural Variants in Cases with Unsolved PRKN-Associated Parkinson's Disease

Agata Fant et al. Mov Disord. .

Abstract

Background: Biallelic mutations in the PRKN gene are a common cause of early-onset Parkinson's disease (EOPD). In addition to single nucleotide variants, structural variants contribute substantially to the mutational profile of PRKN. A significant portion of patients with EOPD remains genetically unsolved.

Objectives: By using short-read whole genome sequencing (sr-WGS), we aimed to uncover complex genetic alterations at the PRKN locus in EOPD cases which tested negative for mutations in Mendelian PD genes with clinical exome sequencing (CES) and multiplex ligation-dependent probe amplification (MLPA).

Methods: We evaluated 498 unrelated EOPD patients, who tested negative using gold-standard diagnostic methods, using sr-WGS. In selected cases, long-read whole genome sequencing (lr-WGS) with Oxford Nanopore technology was employed for an in-depth analysis and validation. The Parkinson's Progression Markers Initiative (PPMI) dataset was interrogated to assess the prevalence of any newly identified elusive pathogenic genetic configurations.

Results: sr-WGS revealed elusive compound heterozygous structural variations, consisting of partially overlapping deletions and duplications within the PRKN gene in three unrelated EOPD cases (two familial, one sporadic). In familial cases, biallelic PRKN structural variants co-segregated with the disease. The exact structure of each variant was resolved using lr-WGS. Similar variants were absent in the large PPMI database, suggesting that they are a rare occurrence.

Conclusions: In this article we describe a rare configuration of compound heterozygous structural variations involving partially overlapping chromosomal regions at the PRKN locus, which are difficult to detect through standard diagnostic genetic technologies. This study highlights the importance of integrating WGS into clinical practice. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: PRKN; Parkinson's disease; WGS; diagnostic; structural variants.

PubMed Disclaimer

References

    1. Lin MK, Farrer MJ. Genetics and genomics of Parkinson's disease. Genome Med 2014;6(6):1–16.
    1. Jankovic J, Tan EK. Parkinson's disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry 2020;91:795–808.
    1. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α‐synuclein gene identified in families with Parkinson's disease. Science 1997;276(5321):2045–2047.
    1. Arienti F, Casazza G, Franco G, et al. Family history in Parkinson's disease: a national cross‐sectional study. Mov Disord Clin Pract 2024;11(11):1434–1440.
    1. Aasly JO. Long‐term outcomes of genetic Parkinson's disease. J Mov Disord 2020;13(2):81–96.

LinkOut - more resources