title: APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.
abstract: BACKGROUND
  Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.
  
  
  RESULTS
  We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.
  
  
  CONCLUSIONS
  Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.|Department of Neurology, Orleans Regional Hospital, Orleans, France.
authors.forename: Hélène-Marie
authors.initials: HM
authors.lastname: Lanoiselée
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: David
authors.initials: D
authors.lastname: Wallon
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rovelet-Lecrux
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Lacour
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Department of Neurology and CNR-MAJ, Lille University Hospital, Lille, France.|Inserm UMR-S 1171, Université Lille Nord de France, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: Department of Neurology and CNR-MAJ, Lille University Hospital, Lille, France.|Inserm UMR-S 1171, Université Lille Nord de France, Lille, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Rollin-Sillaire
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Martinaud
authors.affiliation: Biochemistry Laboratory, Rouen University Hospital, Rouen, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Quillard-Muraine
authors.affiliation: Department of Neurology, Caen University Hospital, Caen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: de la Sayette
authors.affiliation: Department of Neurology, Nantes University Hospital, Nantes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Boutoleau-Bretonniere
authors.affiliation: Department of Neurology, Angers University Hospital, Angers, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Etcharry-Bouyx
authors.affiliation: Department of Neurology, Angers University Hospital, Angers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Chauviré
authors.affiliation: Department of Neurology, Saint Anne University Hospital, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sarazin
authors.affiliation: CNR-MAJ, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; and ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: le Ber
authors.affiliation: CNR-MAJ, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France; and ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC-P6 UMR S 1127 - Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Epelbaum
authors.affiliation: Department of Neurology, Nancy University Hospital, Nancy, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Jonveaux
authors.affiliation: Department of Neurology, Dijon University Hospital, Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rouaud
authors.affiliation: Aix Marseille University, Inserm, INS, Institut de Neurosciences des Systèmes, Marseille, France; AP-HM, Service de Neurologie et Neuropsychologie, CHU Timone, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ceccaldi
authors.affiliation: Aix Marseille University, Inserm, INS, Institut de Neurosciences des Systèmes, Marseille, France; AP-HM, Service de Neurologie et Neuropsychologie, CHU Timone, Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Félician
authors.affiliation: Department of Neurology, Amiens University Hospital Center, Amiens, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Godefroy
authors.affiliation: Department of Neurology and CMRR Lyon University Hospital, Lyon, France.
authors.forename: Maite
authors.initials: M
authors.lastname: Formaglio
authors.affiliation: Department of Neurology and CMRR Lyon University Hospital, Lyon, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Croisile
authors.affiliation: Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Auriacombe
authors.affiliation: Department of Neurology, Besançon University Hospital, Besançon, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Chamard
authors.affiliation: Biochemistry Laboratory, Lille University Hospital, Lille, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.affiliation: Department of Neurology, Grenoble University Hospital, Grenoble, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sauvée
authors.affiliation: Department of Neurology, Montpellier University Hospital, Montpellier, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli-Tosi
authors.affiliation: Department of Neurology, Montpellier University Hospital, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gabelle
authors.affiliation: Department of Neurology, Orleans Regional Hospital, Orleans, France.
authors.forename: Canan
authors.initials: C
authors.lastname: Ozsancak
authors.affiliation: Department of Neurology, Toulouse University Hospital, Toulouse, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Pariente
authors.affiliation: CMRR Paris Nord AP-HP, Hôpital Lariboisière, INSERM, U942, Université Paris Diderot, Sorbonne Paris Cité, UMRS 942, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.affiliation: Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France.|Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005260:Female; D005602:France; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2