Data from the ROPAD study corroborate an association between ITSN1 loss-of-function variants and Parkinson’s disease

We read with interest the recent studies by Skuladottir and colleagues and Cogan and colleagues, which report a novel association between monoallelic loss-of-function (LoF) variants in the ITSN1 gene and risk for Parkinson’s disease (PD) 1 , 2 . The first study observed that heterozygous LoF variants in ITSN1 confer a large risk for developing PD in analyses combining the deCODE, UK Biobank, and Accelerating Medicines Partnership Parkinson’s Disease (AMP-PD) datasets 1 . The second study identified five PD patients from three families who harbored distinct heterozygous frameshift ITSN1 variants and reported their clinical phenotype 2 . Yet another recent study reported similar results in an analysis of the UK Biobank, the AMP-PD, and the All of US cohorts, where they observed an increased risk of PD in individuals with LoF variants in ITSN1 and provided functional evidence in a Drosophila model, showing an interaction between ITSN1 – encoded Intersectin-1 and α-synuclein 3 . Still, the clinical manifestation of PD in patients with LoF variants in ITSN1 remains largely unexplored. We aimed to investigate the reported association of ITSN1 LoF variants with PD in a large independent patient group and to determine whether patients with ITSN1 LoF variants present with a clinically distinct PD form.