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Gene Panel Sequencing Analysis Revealed a Strong Contribution of Rare Coding Variants to the Risk of Parkinson’s Disease in Sporadic Moroccan Patients

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Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder which can be either familial or sporadic. While it is well known that monogenic mutations are not a very common cause of PD, GWAS studies have shown that an additional fraction of the PD heritability could be explained by rare or common variants. To identify the rare variants that could influence the risk of PD in the Moroccan population, a cohort of 94 sporadic PD patients negative for the LRRK2 G2019S mutation was subjected to NGS gene panel sequencing, and gene dosage using the MLPA method. Mean age of onset at enrollment was 51.7 ± 11.51 years, and 60% of patients were men. We identified 70 rare variants under 0.5% of frequency in 16 of the 20 genes analyzed, of which 7 were novel. Biallelic disease-causing variants in genes with recessive inheritance were found in 5 PD cases (5.31%), whereas 13 patients (13.8%) carried likely pathogenic variants in genes with dominant inheritance. Moreover, 8 patients (8.5%) carried a single variant in MAPT or POLG, whereas co-occurrence of rare variants involving more than one gene was observed in 28 patients (30%). PD patients with variants in recessive genes had a younger mean age at onset than patients with dominant ones (33.40 (12.77) vs. 53.15 (6.63), p < 0.001), while their clinical features were similar. However, patients with rare variants in the risk factor genes or in more than one gene tended to have less resting tremor (p < 0.04), but more dystonia (p < 0.006) and dementia (p < 0.002) than those without any rare variants in known PD-associated genes. Our results showed a significant enrichment of rare variants particularly in LRRK2, VPS13C, POLG, and MAPT and underline their impact on the risk of sporadic form of the disease.

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Data Availability

The datasets generated or used in the current study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

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Acknowledgements

We are grateful to all patients and healthy volunteers for their participation in this study.

Funding

The study was supported by the “Ministère de l’Enseignement Supérieur, de la Recherche Scientifique et de la Formation des Cadres” (MESRSFC) of Morocco and the Mohammed V University in Rabat, Morocco.

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Author notes

  1. Imane Smaili and Houyam Tibar contributed equally.

Authors and Affiliations

  1. Research Team in Neurology and Neurogenetics, Center of Genomics of Human Pathologies, Medical School and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco

    Imane Smaili, Mounia Rahmani, Ali Benomar, Wafa Regragui & Ahmed Bouhouche

  2. Department of Neurology and Neurogenetics, Specialties Hospital, CHU Ibn Sina, Rabat, Morocco

    Houyam Tibar, Najlaa Machkour, Hajar Naciri Darai, Naima Bouslam, Ali Benomar, Wafa Regragui & Ahmed Bouhouche

  3. Department of Neurology and Neuropsychology, Specialties Hospital, CHU Ibn Sina, Rabat, Morocco

    Mounia Rahmani

  4. Laboratory of Biostatistics, Clinical and Epidemiological Research, Department of Public Health, Medical School and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco

    Rachid Razine

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  1. Imane Smaili
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Contributions

HT, MR NM HND and WR acquired the clinical data. IS carried out NGS and Sanger experiments, and prepared the figures. AhB performed bioinformatics analysis and interpreted the results. RR performed statistical analysis. AhB and HT wrote the paper. AhB, WR and AlB revised the manuscript. AhB conceptualized and designed the study. All authors reviewed the manuscript.

Corresponding author

Correspondence to Ahmed Bouhouche.

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All research was approved by the ethics committee of biomedical research of Medical School and Pharmacy of Rabat (CERB).

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Smaili, I., Tibar, H., Rahmani, M. et al. Gene Panel Sequencing Analysis Revealed a Strong Contribution of Rare Coding Variants to the Risk of Parkinson’s Disease in Sporadic Moroccan Patients. J Mol Neurosci 73, 391–402 (2023). https://doi.org/10.1007/s12031-023-02128-9

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