Abstract
In the past two decades, genetic studies of familial forms of Parkinson’s disease (PD) have shown evidence that PD has a significant genetic component. Indeed, 12 genes are strongly involved in PD causality, three of them having dominant inheritance and 9 causing early-onset autosomal recessive forms, including 3 with a typical PD and 6 with an atypical parkinsonism. The aim of this study was to determine the genetic basis of familial PD in Moroccan patients. We selected 18 Moroccan index case with familial forms of PD. Patients were first screened for exon-rearrangements by MLPA kit. They were then analyzed by gene panel next-generation sequencing (NGS). Functional variants with minor allele frequencies < 0.5% in public databases were considered potential candidate variants to PD. In the 18 PD patients with a positive family history that were analyzed, MLPA assays identified PRKN deletions in two patients: a homozygous exon 3–5 deletion and a heterozygous exon 4 deletion. Sixteen rare SNV were identified by NGS, four of them were novel. Seven mutations were categorized as pathogenic, five as likely pathogenic, two to be of uncertain significance, and 3 were predicted to be likely benign but may give a weaker pathogenic effect and could contribute to PD since they were found in late-onset PD patients. Rare or novel mutations that could be related to the disease were identified in 72% of these patients (13/18), including nine with bi-allelic pathogenic/likely pathogenic variants in genes causing recessive PD, particularly PRKN and PINK1. Mutations in genes with dominant inheritance were found in 4/18 patients (22%).
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The datasets used and analyzed during the current study are available from the corresponding author upon request.
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Acknowledgments
We are grateful to all patients for their participation in this study and to Dr. Leslie Hunter for improving the English language of the manuscript.
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 “Centre National de Recherche Scientifique et Technique” (CNRST).
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Supplementary Fig. 1
Family pedigree of the eighteen index PD cases studied. a Families with probably autosomal dominant inheritance; b families with probably autosomal recessive inheritance; c families with unspecified inheritance. (PPT 925 kb)
Supplementary Table 1
Comparison between the two NGS gene panels used in this study. (DOCX 13 kb)
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Smaili, I., Tesson, C., Regragui, W. et al. Gene Panel Sequencing Identifies Novel Pathogenic Mutations in Moroccan Patients with Familial Parkinson Disease. J Mol Neurosci 71, 142–152 (2021). https://doi.org/10.1007/s12031-020-01635-3
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DOI: https://doi.org/10.1007/s12031-020-01635-3