ObjectiveImpaired lysosomal degradation of α‐synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD.MethodsWe investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next‐generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes.ResultsWe confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C.ConclusionRare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome‐wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society

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Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epilepsy characterized by new‐onset refractory status epilepticus with a prior febrile infection. We performed exome sequencing in 50 individuals with FIRES, including 27 patient–parent trios and 23 single probands, none of whom had pathogenic variants in established genes for epilepsies or neurodevelopmental disorders. We also performed HLA sequencing in 29 individuals with FIRES and 529 controls, which failed to identify prominent HLA alleles. The genetic architecture of FIRES is substantially different from other developmental and epileptic encephalopathies, and the underlying etiology remains elusive, requiring novel approaches to identify the underlying causative factors.