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

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.