Objective: Identify genomic variants present in Argentinean PSP cases and assess their genetic background.

Background: Progressive supranuclear palsy (PSP) is a primary tauopathy with low global prevalence. Monogenic cases have been related mainly with variants in the MAPT gene. Furthermore, genetic risk factors for PSP vary significantly across different populations, underscoring the need for more inclusive genetic studies across populations with admixed and underrepresented populations. 

The Argentine Consortium for Research on Primary Tauopathies (CAITauP) is building a resource for studying tauopathies such as PSP and CBD in South American populations in collaboration with GP2 and CurePSP Genetic Registry.

Method: CAITauP is currently enrolling patients and collecting DNA samples from Argentine patients. We recruited and enrolled 26 patients with clinical diagnosis of PSP, 18 patients with clinical diagnosis of PD and 6 healthy controls. DNA was extracted from blood and brain samples and sent for sequencing with support from the GP2 Parkinsonism-Plus Working Group.

We thoroughly examined our inception case as a proof of concept for CAITauP, conducting clinical, histopathological and genetic analyses. Expansion of this approach to our first cohort, searching for related pathogenic variants and determining MAPT haplotypes.

After receiving the sequencing data, we plan to annotate variants and identify potentially relevant ones by applying ACMG criteria. In addition, we will analyze individual genetic parameters, such as relatedness and ancestry. Global ancestry will be determined using supervised PCA and Local ancestry will be inferred by using selected referenced panels from the 1000 Genomes Project.

Results: Our inception case presented a variant of interest located in the SQSTM1 gene (NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)), which was classified as a VUS. With our first cohort’s samples sequencing ongoing, we aim to present a full genetic report on these patients. This includes demographic data, relevant variants and ancestry studies.

Conclusion: We are performing an initial genetic screening on our first cohort of local PSP patients, focusing at the moment on individual variants and genetic ancestry. Recruitment is ongoing on a permanent basis with the objective of reaching a significant number of cases, allowing to run a case-control analysis.

References: Ruiz-Barrio, I., Horta-Barba, A., Illán-Gala, I., Kulisevsky, J., & Pagonabarraga, J. (2022). Genotype–phenotype correlation in progressive supranuclear palsy syndromes: clinical and radiological similarities and specificities. Frontiers in neurology, 13, 861585.

Angel, M. J., Mizraji, G. F., Gomez-Arevalo, G., Silvia, G., Gonzalez-Toledo, M. E., Elena, A., … & Blas, C. (2025). Prospective longitudinal cohort of Argentinean patients with progressive supranuclear palsy and corticobasal syndrome: A platform for epidemiological and translational research. Clinical Parkinsonism & Related Disorders, 12, 100339.

Wen, Y., Zhou, Y., Jiao, B., & Shen, L. (2021). Genetics of progressive supranuclear palsy: a review. Journal of Parkinson’s Disease, 11(1), 93-105.
Leal, T. P., Waldo, E., Duarte-Zambrano, F., Inca-Martinez, M., Ramchandra, J., Chaparro-Solano, H. M., Anello, A. E., Borda, V., Gouveia, M. H., Teixeira-Dos-Santos, D., Reyes-Pérez, P., Gatto, E. M., Santos-Lobato, B. L., Eufraseo, G., Letro, G. H., Arboleda, G., Bernal-Pacheco, O., Orozco, J. L., Munoz, B., Chana-Cuevas, P., … Mata, I. F. (2025). Genotype-phenotype association study conducted on LARGE-PD reveals novel loci associated with Parkinson’s Disease. medRxiv : the preprint server for health sciences, 2025.07.18.25331793.

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L., & ACMG Laboratory Quality Assurance Committee (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine : official journal of the American College of Medical Genetics, 17(5), 405–424.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genomic-analysis-of-an-argentinean-psp-cohort/