Royal College of Surgeons in Ireland
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Genotype-phenotype correlation in PRKN-associated parkinson's disease.pdf (2.51 MB)

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

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journal contribution
posted on 2024-05-02, 07:40 authored by Poornima Jayadev MenonPoornima Jayadev Menon, French Parkinson disease Genetics Study Group (PDG)

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

Funding

‘Investissements d’Avenir’ ANR-10-IAIHU-06

France Parkinson Patient Organisation (grant PRECISE-PD)

Edmond J. Safra fellowship in Movement Disorders

Edmond J. Safra Foundation

Aligning Science Across Parkinson’s (Grant Number: ASAP-000478) through the Michael J. Fox Foundation for Parkinson’s Research (MJFF)

Intramural Research Program of the NINDS, National Institutes of Health: project number 1ZIA-NS003169

History

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available, as it contain information that could compromise the privacy of study participants.

Comments

The original article is available at https://www.nature.com/

Published Citation

Menon PJ. et al. Genotype-phenotype correlation in PRKN-associated Parkinson's disease. NPJ Parkinsons Dis. 2024;10(1):72

Publication Date

29 March 2024

PubMed ID

38553467

Publisher

Nature Publishing Group

Version

  • Published Version (Version of Record)