Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which genetic diagnosis is still challenging. We have recently reported the identification of rare new gene variants in PD patients that support polygenic contribution to the disease. Here we report the identification of novel PD genes and a novel protocol for predictive analysis of PD risk.The study includes the whole exome data of 22 PD families, 804 unrelated PD and 282 healthy subjects.Family-based approach identified rare and disrupting variants, in 44 candidate genes, co-inherited by affected relatives. The analysis of the entire cohort discovered a significant excess of rare and deleterious variants in PD patients in 5 novel PD genes, known as ANKK1, ANKRD50, GRK5, PACSIN1 and VPS8, highly expressed in dopaminergic neurons, and involved in signal transduction pathways and in endocytic recycling. In these genes, we identified both rare likely pathogenic variants, altering protein structure and dynamics, as well as frequent variants associated with PD risk.We demonstrated that the co-inheritance of multiple rare variants (≥ 2) in a panel of 37 PD genes, may predict disease risk in about 26% of patients, both familial and sporadic cases, with high specificity (> 90%; p = 3.23 x10-9). Patients carrying multiple rare variants showed dyskinesia induced by levodopa treatment (p=0.004), severe cognitive impairment (p=0.009) and an earlier age at onset of the disease (p=0.01). These data provide novel insights into the genetic of PD and may be relevant for its prediction, diagnosis and treatment.