Objective: We describe clinical, genealogic and genetic studies in several families with multi-incident Parkinson’s disease (PD).

Background: PD is a multifactorial trait for which components may be best elucidated within relatively homogeneous population isolates. French Canadians, in the Eastern region of Quebec Province, are descendants of a founder population. Recessively-inherited disorders are more prevalent, and pathogenic mutations have been identified in several genes.

Methods: Clinical and genealogic data was obtained for patients and their associated pedigrees, with established criteria and standardized assessments. All patients with early-onset and familial PD were analyzed for copy number variation in parkin (PARK2), PINK1, DJ-1, ATP13A2 and SNCA using multiplex-probe ligation amplification. Frequently reported pathogenic mutations in GBA, LRRK2 and SNCA were also examined by genotyping all affected family members. Polynucleotide repeats within SCA2, SCA3, SCA12 and SCA17 were also scored. A multi-ethic genome array (MEGA, 1.8M genotypes) was assessed in 38 individuals including familial probands, additional affected and unaffected relatives. Whole exome sequencing (58Mb) was completed for the same subjects, and variability in genes linked and/or associated with PD was examined. Putatively pathogenic mutations were validated by Sanger sequencing. Segregation analysis and subsequent linkage simulations were performed.

Results: Twenty-two families are included in this study (sibship range 2-5) with mean age of onset 56.5 ± 9.0 years (SD), range 35–70 years, gender ratio was 1.8:1 (M:F). Copy number variation in parkin (PARK2), PINK1, DJ-1, ATP13A2 and SNCA were negative. Frequently reported pathogenic mutations in GBA, LRRK2 and SNCA were excluded by genotyping in all affected family members. Polynucleotide repeats within SCA2, SCA3, SCA12 and SCA17 were all within the normal range. However, a SNCA duplication was identified in one sporadic case of a 51 year old male, 48 at onset with a typical akineto rigid right sided onset and early fluctuation on L-Dopa, MOCA at 3 years is 25/30. Comparative genetic analysis with SNCA multiplication has been performed.

Conclusions: Our data suggest a novel genetic etiology for PD in this French Canadian population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/familial-parkinsons-disease-in-the-province-of-quebec/