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Heterozygous and Homozygous Variants in SORL1 Gene in Alzheimer’s Disease Patients: Clinical, Neuroimaging and Neuropathological Findings

In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer’s disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that...

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Detalles Bibliográficos
Autores principales: Alvarez-Mora, Maria Isabel, Blanco-Palmero, Victor Antonio, Quesada-Espinosa, Juan Francisco, Arteche-Lopez, Ana Rosa, Llamas-Velasco, Sara, Palma Milla, Carmen, Lezana Rosales, Jose Miguel, Gomez-Manjon, Irene, Hernandez-Lain, Aurelio, Jimenez Almonacid, Justino, Gil-Fournier, Belén, Ramiro-León, Soraya, González-Sánchez, Marta, Herrero-San Martín, Alejandro Octavio, Pérez-Martínez, David Andrés, Gómez-Tortosa, Estrella, Carro, Eva, Bartolomé, Fernando, Gomez-Rodriguez, Maria Jose, Sanchez-Calvin, María Teresa, Villarejo-Galende, Alberto, Moreno-Garcia, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024679/
https://www.ncbi.nlm.nih.gov/pubmed/35457051
http://dx.doi.org/10.3390/ijms23084230
Descripción
Sumario:In the last few years, the SORL1 gene has been strongly implicated in the development of Alzheimer’s disease (AD). We performed whole-exome sequencing on 37 patients with early-onset dementia or family history suggestive of autosomal dominant dementia. Data analysis was based on a custom panel that included 46 genes related to AD and dementia. SORL1 variants were present in a high proportion of patients with candidate variants (15%, 3/20). We expand the clinical manifestations associated with the SORL1 gene by reporting detailed clinical and neuroimaging findings of six unrelated patients with AD and SORL1 mutations. We also present for the first time a patient with the homozygous truncating variant c.364C>T (p.R122*) in SORL1, who also had severe cerebral amyloid angiopathy. Furthermore, we report neuropathological findings and immunochemistry assays from one patient with the splicing variant c.4519+5G>A in the SORL1 gene, in which AD was confirmed by neuropathological examination. Our results highlight the heterogeneity of clinical presentation and familial dementia background of SORL1-associated AD and suggest that SORL1 might be contributing to AD development as a risk factor gene rather than as a major autosomal dominant gene.