Objective: To examine the clinical and neuropathological features of carriers of loss-of-function (LoF) variants in ITSN1.

Background: Intersectin-1 (ITSN1) is a large multidomain protein involved in endocytosis and synaptic vesicle recycling. LoF variants in ITSN1 have previously been associated with neurodevelopmental phenotypes but recent studies have identified an association between protein-truncating variants in ITSN1 and Parkinson’s Disease risk . To date no pathological or biochemical characterisation of variant carriers has been reported to support the role of these variants in PD pathogenesis.

Method: Whole Genome or Exome Sequencing Data from 64,732 PD cases and 30,848 controls across 3 cohorts (GP2 Release 11, UCL Queen Square Genomics database and the UK Brain Bank Network) was screened for LoF variants in ITSN1 based on predicted consequence or Loss-of-Function Transcript estimator (LOFTEE) annotation. Basic clinical information was gathered for each carrier. Variants were confirmed by Sanger Sequencing. Neuropathological examination was performed in three post-mortem cases.

Results: 16 LoF variants in 15 PD cases and 1 control were identified. Affected carriers of LoF variants in ITSN1 had a mean age at onset of 53.5 years and age at diagnosis of 55.7 years. 7 individuals had a positive family history of PD or a neurodevelopmental disorder.  Initial phenotype varied with typical asymmetric parkinsonism present in 5 cases and Dementia with Lewy Bodies in 1 case.  Non-motor features were present in 4 cases including anosmia, constipation, urinary incontinence and REM-sleep behaviour disorder. One individual demonstrated self-mutilatory behaviours but there was no clear history of neurodevelopmental disorders in carriers. Neuropathological examination of 3 variant carriers including the clinically defined control individual showed typical Lewy Body Pathology.

Conclusion: Carriers of LoF variants in ITSN1 demonstrate variable age at onset and family history of PD or neurodevelopmental disorders. The most common clinical phenotype is classical asymmetric parkinsonism with mild non-motor features. Neuropathological features are classical for Lewy Body Pathology. Further work will characterise the effect of these variants at the protein and RNA levels.

References: 1. Bruel AL, Vitobello A, Thiffault I, et al. ITSN1: a novel candidate gene involved in autosomal dominant neurodevelopmental disorder spectrum. Eur J Hum Genet. 2022;30(1):111-116.
2. Liaqat K, Treat K, Wilson TE, Conboy E, Vetrini F. Further evidence of involvement of ITSN1 in autosomal dominant neurodevelopmental disorder. Clin Genet. 2024;105(4):455-456.
3. Spargo TP, Sands CF, Juan IR, et al. Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease. Cell Rep. 2025;44(3):115355.
4. Skuladottir AT, Tragante V, Sveinbjornsson G, et al. Loss-of-function variants in ITSN1 confer high risk of Parkinson’s disease. NPJ Parkinsons Dis. 2024;10(1):140.
5. Cogan G, Tesson C, Welment L, et al. Should ITSN1 be considered as a Mendelian Parkinson’s disease gene? Description of three novel families. NPJ Parkinsons Dis. 2025;11(1):295.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/intersectin-1-itsn1-loss-of-function-variants-in-parkinsons-disease-clinical-phenotypes-and-neuropathological-insights/