Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort

LRRK2, SNCA, andVPS35are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence ofLRRK2, SNCA, andVPS35mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays forLRRK2Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenicLRRK2variants (7.6%), including 136 with the Gly2019Ser mutation, 19 withSNCApoint mutations or genomic rearrangements (1.1%), and three with theVPS35Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2-2.4],p= 0.001). PD patients withLRRK2variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1],p= 0.03), whereas those withSNCAmutations tended to have earlier age at onset disease (<= 50 years,p= 0.06). The clinical features ofLRRK2carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.