Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease

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...

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Autores: Andersen, OM; de Waal, MWJ; Monti, G; Tesi, N; Jensen, AMG; De Geus, C; van Spaendonk, R; Vogel, M; Ahmad, S; Amin, N; Amouyel, P; Beecham, GW; Bellenguez, C; Berr, C; Bis, JC; Boland, A; Bossù, P; Bouwman, F; Bras, J; Charbonnier, C; Clarimon, J; Cruchaga, C; Daniele, A; Dartigues, JF; Debette, S; Deleuze, JF; Denning, N; Destefano, AL; Dols-Icardo, O; van Duijn, CM; Farrer, LA; Fernández, MV; van der Flier, WM; Fox, NC; Galimberti, D; Genin, E; Gille, JJP; Grenier-Boley, B; Grozeva, D; Guen, YL; Guerreiro, R; Haines, JL; Holmes, C; Hummerich, H; Ikram, MA; Ikram, MK; Kawalia, A; Kraaij, R; Lambert, JC; Lathrop, M; Lemstra, AW; Lleo, A; Myers, RM; Mannens, MMAM; Marshall, R; Martin, ER; Masullo, C; Mayeux, R; Mead, S; Mecocci, P; Meggy, A; Mol, MO; Nacmias, B; Naj, AC; Napolioni, V; Cochran, JN; Nicolas, G; Pasquier, F; Pastor, P; Pericak-Vance, MA; Pijnenburg, YAL; Piras, F; Quenez, O; Ramirez, A; Raybould, R; Redon, R; Reinders, MJT; Richard, AC; Riedel-Heller, SG; Rivadeneira, F; van Rooij, JGJ; Rousseau, S; Ryan, NS; Sanchez-Juan, P; Schellenberg, GD; Scheltens, P; Schott, JM; Seshadri, S; Sie, D; Sims, R; Sistermans, EA; Sorbi, S; van Swieten, JC; Tijms, B; Uitterlinden, AG; Visser, PJ; Wagner, M; Wallon, D; Wang, LS; Williams, J; Yokoyama, JS; Zarea, A; van der Lee, SJ; Olsen, JG; Hulsman, M; Holstege, H
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2025
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p20707
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20707
Nivel de acceso:Acceso abierto
Palabra clave:SORL1
SORLA
Alzheimer's disease
Genetics
Penetrance
Age at onset
Rare variants
Disease risk
Alzforum mutation database
Domain-mapping disease-mutations
Sumario: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 similar to 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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