Massive Parkinson’s Genetics Study Confirms Rare Gene Variants Raise Disease Risk

A scientific dispute over one of the most intriguing new genetic leads in Parkinson’s disease research has taken a decisive turn. In a reply published in npj Parkinson’s Disease, a team of French researchers led by Guillaume Cogan of the Paris Brain Institute has welcomed new evidence from an international collaboration that appears to settle the central question: loss-of-function variants in the gene ITSN1 really are associated with a substantially increased risk of developing Parkinson’s disease. The exchange, framed as a formal Matters Arising discussion, highlights both the power and the limitations of large-scale genetic cohort studies, and it raises uncomfortable questions about what clinicians should tell patients and families who carry these variants.

The controversy began with a series of three studies pointing to ITSN1 as a Parkinson’s disease susceptibility gene. Loss-of-function variants are mutations that disable a gene’s protein product, and when such variants occur in ITSN1, the resulting condition is predicted to be haploinsufficiency: having only one working copy of the gene is not enough for normal cellular function. The most recent and most compelling piece of evidence came from Ganoza and colleagues, who screened the Rostock International Parkinson’s Disease study, known as ROPAD, a cohort that includes 8,660 participants with Parkinson’s disease. Their analysis globally replicated the earlier findings and established that ITSN1 loss-of-function carriers represent roughly one to two individuals per thousand with Parkinson’s disease suspected of having a genetic cause.

The scale of the risk elevation is what makes ITSN1 so remarkable. According to the reply, a carrier of an ITSN1 loss-of-function variant faces between five and fifteen times the risk of developing Parkinson’s disease compared with a non-carrier. That places ITSN1 among the strongest genetic risk factors identified for the condition, in a category typically reserved for well-known genes such as LRRK2 and GBA1. Equally notable is the clinical picture: the Parkinson’s disease that emerges in ITSN1 carriers does not differ significantly from classical, non-genetic Parkinson’s disease, meaning carriers present with the familiar motor syndrome rather than an exotic or easily distinguishable variant of the illness.

The Paris team had approached the gene from a different angle. After identifying three pedigrees with ITSN1 loss-of-function variants in their own cohort at the Paris Brain Institute, two of which showed positive segregation of the variant with disease across generations, they hypothesized that ITSN1 might act as a Mendelian gene. In genetics, a Mendelian gene is one in which a single mutation is sufficient to cause disease in a predictable inheritance pattern, typically autosomal dominant or recessive, as opposed to risk genes that merely shift probabilities. If ITSN1 were Mendelian, families carrying one mutation would show the disease appearing in multiple relatives in an orderly pattern, and genetic counseling would follow established rules for dominant disorders.

Ganoza and colleagues tested this hypothesis using the ROPAD data and found it wanting. The frequency of positive family history among ITSN1-associated Parkinson’s disease individuals did not differ significantly from that of individuals without ITSN1 loss-of-function variants: 23 percent versus 34 percent, a difference that failed to reach statistical significance with a p-value of 0.5. On its face, this argues against a straightforward Mendelian model, since a true dominant gene should produce a conspicuously elevated rate of affected relatives. But the Paris group, in their reply, argues that the comparison is less conclusive than it appears, and they raise two methodological concerns that deserve careful attention from anyone following the genetics of neurodegenerative disease.

The first concern involves the composition of the ROPAD cohort itself. The Paris researchers noticed that the frequency of positive family history among non-carriers, 34 percent, seems higher than what would be expected for classical Parkinson’s disease in the general population. The likely explanation, they suggest, is recruitment bias: the cohort was enriched for individuals already suspected of having a genetic etiology for their disease. The authors of the original analysis acknowledged as much, noting that the early average age at onset in their cohort, 55 years, supports the presence of such a bias. Age at onset is a classic marker in Parkinson’s genetics, since earlier-onset disease is more often genetically driven, and a cohort selected for early onset will naturally over-represent familial cases on both sides of any genetic comparison.

The second concern is more fundamental: the ROPAD analysis did not provide pedigrees, or familial structures, for the 13 individuals carrying ITSN1 loss-of-function variants. Without those family trees, the field cannot know how many relatives were actually affected in individuals reporting a positive family history, whether the inheritance pattern suggested autosomal dominance or recessivity, or whether segregation analysis was performed to confirm that the variant tracked with disease. The Paris team offers a plausible alternative explanation for the negative result: several of the loss-of-function variants may have arisen de novo, meaning spontaneously in the carrier rather than being inherited, which would explain why family history was not always positive. There is also growing evidence of reduced penetrance for ITSN1, meaning that not everyone who carries a damaging variant develops disease. Sorting out these possibilities, the reply argues, will be essential before any conclusion can be drawn about the Mendelian hypothesis, and before accurate genetic counseling can be offered to carriers and their relatives.

The counseling challenge is compounded by a feature that makes ITSN1 genuinely unusual among Parkinson’s genes. Loss-of-function variants in ITSN1 are associated not only with Parkinson’s disease but also with neurodevelopmental disorders, conditions that manifest in infancy or childhood. Other recently discovered genes, such as PSMF1 and EPG5, similarly produce a clinical spectrum running from early-onset neurodevelopmental disorders to later-onset Parkinsonism, but in those cases the type of variant usually differs, with truncating variants producing more severe phenotypic consequences than missense variants, which change only a single amino acid. For ITSN1, by contrast, only loss-of-function variants have been reported in Parkinson’s disease, and all are predicted to cause haploinsufficiency. That raises a puzzle the reply states plainly: why could the same mechanism, the loss of one functional copy of the gene, lead to two such distinct phenotypes, a childhood neurodevelopmental disorder in some carriers and a late-life neurodegenerative disease in others?

One hypothesis involves the protein itself. Two isoforms of the ITSN1 protein product, Intersectin-1, are currently known, and the location of a loss-of-function variant, whether it disrupts one isoform or both, could in principle explain the variable expressivity. However, the reply notes that variants identified in both diseases appear to affect both isoforms, so this explanation alone does not suffice, and, as Ganoza and colleagues hypothesized, other modifying factors remain to be discovered. The Paris team sketches several research strategies to find them. Functional studies using biological materials from ITSN1 loss-of-function carriers are already underway to clarify why the loss of Intersectin-1 predisposes to Parkinson’s disease, a question that persists even though the protein’s many roles, particularly as a scaffold for membrane-associated processes such as endocytosis, have been extensively characterized. A second approach would leverage large Parkinson’s disease datasets to compare genetic variant frequencies, environmental exposures, and lifestyle habits between unaffected elderly controls and carriers, with particular attention to ITSN2, the gene encoding the second member of the intersectin family, whose protein can compensate for some defects caused by reduced ITSN1 expression. The consistency of the average age at onset across studies should help researchers choose an appropriate inclusion age for controls. Beyond loss-of-function variants, certain missense variants in the missense-constrained region of the gene, spanning amino acids 1199 to 1722, have been linked to neurodevelopmental disorders, and their possible role in Parkinson’s disease has not yet been explored.

Why does this academic debate matter beyond the laboratory? The reply closes with a warning about clinical practice. Genetic testing is becoming more accessible, and ITSN1 loss-of-function variants are not so rare, so they will increasingly surface as incidental findings in people tested for unrelated reasons. For a neurologically unaffected adult, the counseling challenge resembles that of a pathogenic LRRK2 or severe GBA1 variant, both of which carry elevated risk with incomplete penetrance. But prenatal detection is a different matter entirely. A carrier fetus could face a neurodevelopmental disorder, Parkinson’s disease in later life, or possibly no ITSN1-related neurological disorder at all, a range of outcomes so wide and so uncertain that it could make decisions about pregnancy continuation agonizing for prospective parents. Having confirmed the association between ITSN1 and Parkinson’s disease through the ROPAD replication, the Paris team argues that the field now faces an urgent need to resolve the questions of penetrance, expressivity, and inheritance pattern, not only to advance the science of neurodegeneration but to give families the accurate, honest information they will inevitably demand as this gene enters routine clinical testing.

Subject of Research: Association between ITSN1 loss-of-function variants and Parkinson's disease risk and inheritance

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

Article References: Cogan, G., Tesson, C., Welment, L., Clot, F., LeGuern, E., Lanore, A., Dürr, A., Cormier-Dequaire, F., Debilly, B., Planes, M., Mangone, G., Lesage, S., & Brice, A. (2026). Reply to: Data from the ROPAD study corroborate an association between ITSN1 loss-of-function variants and Parkinson’s disease. npj Parkinson's Disease, 12(1), Article 236. https://doi.org/10.1038/s41531-026-01470-0

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01470-0

Keywords: Parkinson's disease, ITSN1, genetics, loss-of-function variants, ROPAD study, haploinsufficiency, neurodevelopmental disorders, genetic counseling, reduced penetrance, Mendelian inheritance, LRRK2, GBA1