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

We have read with great interest the “Matters Arising” text of Ganoza and colleagues. After three articles1,2,3 demonstrating an association between Loss-of-Function (LoF) ITSN1 variants and Parkinson’s Disease (PD), the authors screened the Rostock International Parkinson’s Disease cohort, including 8660 PD participants. They globally replicate previous findings.

ITSN1 LoF carriers represent 1-2/1000 PD individuals suspected to have a genetic cause. The increased risk of developing PD for an ITSN1 LoF variant carrier compared to a non-carrier ranges between 5 and 151,2, and the resulting phenotype does not differ significantly from that of classical PD. Of note, regarding the latter, the authors do not provide information about potential atypical neurological symptoms (cerebellar ataxia, cognitive impairment, etc.).

Upon the identification of three pedigrees with ITSN1 LoF variants in our cohort from the Paris Brain Institute, among which two had a positive segregation, we raised the hypothesis that ITSN1 could also act as a Mendelian gene3. Not supporting this hypothesis, Ganoza and colleagues found that the frequency of positive family history among ITSN1-PD individuals did not differ significantly from ITSN1 LoF negative individuals (23% vs. 34%, respectively, p = 0.5). However, two comments should be made.

First, we noticed that the frequency of positive family history in non-carriers seems higher (34%) compared to what would be the actual frequency for classical PD4,5, likely because their cohort is biased towards PD individuals suspected of having a genetic etiology of PD. As acknowledged by the authors, the early age at onset of their cohort (55 years) is in favor of a recruitment bias. Second, they did not provide pedigrees (or familial structure) for the 13 individuals carrying LoF ITSN1 variants, therefore we do not know how many relatives were affected in individuals with a positive family history, whether the pedigrees indicated an autosomal dominant or recessive inheritance and whether segregation was performed.

A possibility is that several of these LoF occurred de novo, explaining why family history was not always positive. In addition, there is growing evidence of reduced penetrance for ITSN1. Addressing these elements will be essential to conclude about the Mendelian hypothesis and provide accurate genetic counseling.

While genetic counseling for ITSN1 appears to be as challenging as for LRRK2 and GBA1, both also associated with reduced penetrance, another important element that is specific to ITSN1 further complicates it. Indeed, ITSN1 LoF variants were not only associated with PD but also to neurodevelopmental disorders (NDD)6. While other recently discovered genes such as PSMF1 and EPG5 are similarly responsible for a clinical spectrum featuring infantile/childhood onset disorder including NDD to later onset PD7,8,9, the type of variants are usually not the same; truncating variants having more severe phenotypic consequences than missense variants.