Objective: To investigate the genetic architecture of PD in North Africa, focusing on Tunisian families, and to identify novel genes and variants using whole-genome approaches.

Background: Despite the identification of several disease-causing genes in Parkinson’s disease (PD), some patients with either a positive family history or apparently sporadic disease lack a defined genetic etiology, suggesting yet unidentified monogenic causes.

Method: As part of the Global Parkinson’s Genetics Program (GP2), we enrolled 38 PD patients from 34 Tunisian families from the National Institute Mongi Ben Hamida of Neurology. All underwent short-read whole-genome sequencing, NeuroBooster array (NBA) genotyping, bioinformatic and segregation analyses to identify known pathogenic and novel PD-associated variants in established and candidate genes. Individuals without a genetic diagnosis after short-read sequencing will undergo Oxford Nanopore long-read sequencing and Bionano optical genome mapping to detect structural and genomic alterations missed by standard methods. Also, genetic screening will be done in 230 North African individuals (189 PD, 41 controls) with Middle Eastern ancestry using GP2 NBA R11 data. As a proof of concept, LRRK2 variants were extracted, and will be followed by broader analyses to identify known and novel PD-associated variants in this population.

Results: First, in the initial screening of Tunisian families, we detected known pathogenic variants in 10 patients (PINK1 p.Gln456Ter: N=5, LRRK2 p.Gly2019Ser: N=3, RAB32 p.Ser71Arg: N=1, GCH1 p.His210Leu: N=1), while 28/38 remained without a known genetic cause. Additional families and relatives from previously enrolled unsolved cases were recruited, yielding 95 participants (28 affected, 58 unaffected, 9 with other neurological diseases), who are undergoing genetic and segregation analyses. Second, LRRK2 genetic screening of North African patients identified the p.Gly2019Ser pathogenic variant in 1 control (2.78%) and 38 PD patients (21.71%). No other pathogenic or likely pathogenic LRRK2 variant was found.

Conclusion: This study will expand the genetic characterization of familial and non-familial PD in North Africa, mainly in Tunisia. Our findings highlight LRRK2 p.Gly2019Ser as a key contributor to monogenic PD in this population. Continued recruitment and investigation of unresolved families will lay the groundwork for discovering novel PD genes and new pathogenic mechanisms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-the-genetic-architecture-of-parkinsons-disease-in-north-africa/