Causative mutations and genetic risk factors ...
Document type :
Article dans une revue scientifique: Article original
DOI :
PMID :
Permalink :
Title :
Causative mutations and genetic risk factors in sporadic early onset alzheimer''s disease before 51 years
Author(s) :
Lacour, Morgane [Auteur]
Quenez, Olivier [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Salomon, Bruno [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Quillard-Muraine, Muriel [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Zarea, Aline [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Magnin, Eloi [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Campion, Dominique [Auteur]
Hannequin, Didier [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Quenez, Olivier [Auteur]
Rovelet-Lecrux, Anne [Auteur]
Salomon, Bruno [Auteur]
Rousseau, Stéphane [Auteur]
Richard, Anne-Claire [Auteur]
Quillard-Muraine, Muriel [Auteur]
Pasquier, Florence [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rollin-Sillaire, Adeline [Auteur]
Martinaud, Olivier [Auteur]
Zarea, Aline [Auteur]
De La Sayette, Vincent [Auteur]
Boutoleau-Bretonniere, Claire [Auteur]
Etcharry-Bouyx, Frederique [Auteur]
Chauvire, Valerie [Auteur]
Sarazin, Marie [Auteur]
Le Ber, Isabelle [Auteur]
Epelbaum, Stéphane [Auteur]
Jonveaux, Therese [Auteur]
Rouaud, Olivier [Auteur]
Ceccaldi, Mathieu [Auteur]
Godefroy, Olivier [Auteur]
Formaglio, Maite [Auteur]
Croisile, Bernard [Auteur]
Auriacombe, Sophie [Auteur]
Magnin, Eloi [Auteur]
Sauvee, Mathilde [Auteur]
Marelli-Tosi, Cecilia [Auteur]
Gabelle, Audrey [Auteur]
Pariente, Jeremie [Auteur]
Paquet, Claire [Auteur]
Boland, Anne [Auteur]
Deleuze, Jean-François [Auteur]
Campion, Dominique [Auteur]
Hannequin, Didier [Auteur]
Nicolas, Gael [Auteur]
Wallon, David [Auteur]
Journal title :
Journal of Alzheimer's disease . JAD
Abbreviated title :
J. Alzheimers Dis.
Publication date :
2019-07-25
ISSN :
1875-8908
English keyword(s) :
PSEN1
APP
cerebrospinal fluid biomarkers (APOE)
early onset Alzheimer''s disease
genetics
PSEN2
APP
cerebrospinal fluid biomarkers (APOE)
early onset Alzheimer''s disease
genetics
PSEN2
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic ...
Show more >BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSIONS: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.Show less >
Show more >BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSIONS: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
CHU Lille
CNRS
Inserm
Université de Lille
CNRS
Inserm
Université de Lille
Collections :
Research team(s) :
Troubles cognitifs dégénératifs et vasculaires
Submission date :
2019-11-27T14:33:12Z