Background: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. Methods: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. Results: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Conclusion: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.
Andersen, O. M., De Waal, M. W. J., Monti, G., Tesi, N., Jensen, A. M. G., De Geus, C., Van Spaendonk, R., Vogel, M., Ahmad, S., Amin, N., Amouyel, P., Beecham, G. W., Bellenguez, C., Berr, C., Bis, J. C., Boland, A., Bossù, P., Bouwman, F., Bras, J., Charbonnier, C., Clarimon, J., Cruchaga, C., Daniele, A., Dartigues, J., Debette, S., Deleuze, J., Denning, N., Destefano, A. L., Dols-Icardo, O., Van Duijn, C. M., Farrer, L. A., Fernández, M. V., Van Der Flier, W. M., Fox, N. C., Galimberti, D., Genin, E., Gille, J. J. P., Grenier-Boley, B., Grozeva, D., Guen, Y. L., Guerreiro, R., Haines, J. L., Holmes, C., Hummerich, H., Arfan Ikram, M., Kamran Ikram, M., Kawalia, A., Kraaij, R., Lambert, J., Lathrop, M., Lemstra, A. W., Lleó, A., Myers, R. M., Mannens, M. M. A. M., Marshall, R., Martin, E. R., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Meggy, A., Mol, M. O., Nacmias, B., Naj, A. C., Napolioni, V., Nicholas Cochran, J., Nicolas, G., Pasquier, F., Pastor, P., Pericak-Vance, M. A., Pijnenburg, Y. A. L., Piras, F., Quenez, O., Ramirez, A., Raybould, R., Redon, R., Reinders, M. J. T., Richard, A., Riedel-Heller, S. G., Rivadeneira, F., Van Rooij, J. G. J., Rousseau, S., Ryan, N. S., Sanchez-Juan, P., Schellenberg, G. D., Scheltens, P., Schott, J. M., Seshadri, S., Sie, D., Sims, R., Sistermans, E. A., Sorbi, S., Van Swieten, J. C., Tijms, B., Uitterlinden, A. G., Visser, P. J., Wagner, M., Wallon, D., Wang, L., Williams, J., Yokoyama, J. S., Zarea, A., Van Der Lee, S. J., Olsen, J. G., Hulsman, M., Holstege, H., Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease, <<MOLECULAR NEURODEGENERATION>>, 2025; 20 (1): N/A-N/A. [doi:10.1186/s13024-025-00907-z] [https://hdl.handle.net/10807/330416]
Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease
Daniele, Antonio;Masullo, Carlo;
2025
Abstract
Background: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. Methods: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. Results: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. Conclusion: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.
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