Indication for molecular testing by multiplex ligation-dependent probe amplification in parkinsonism.

Abstract

The monogenic forms of Parkinson's disease represent less than 10% of familial cases and a still lower frequency of sporadic cases. However, guidelines to orient genetic testing are lacking. We aim to establish the interest of multiplex ligation-dependent probe amplification as a primary screening test and to propose clinical criteria to guide genetic diagnostic tests for patients with suspected Mendelian Parkinson's disease. We recruited 567 patients with parkinsonism from 547 unrelated families and performed two multiplex ligation-dependent probe amplifications for each. We confirmed all pathogenic G2019S variants in the LRRK2 gene by Sanger sequencing and screened the PRKN gene for a second mutation in cases of one heterozygous structural variant in the PRKN gene. The performance of multiplex ligation-dependent probe amplifications was 51/567 (9%) for the entire cohort and included 27 (4.8%) LRRK2 G2019S mutations, 19 (3.4%) PRKN mutations, and 5 (0.9%) SNCA locus duplications. The variables significantly associated with a positive test in the total cohort were North African ancestry (p < 0.0001), female sex (p = 0.004), and younger age at onset (p < 0.0008). Retrospective analysis allowed us to refine our indication criteria: (i) North African ancestry, (ii) an age at onset < 40, or (iii) a familial history of parkinsonism with at least one affected first-degree relative. Our study highlights the interest of MLPA testing for other parkinsonisms cases with a family history, especially for patients with dementia with Lewy bodies or a multiple system atrophy-like phenotype.