1. Primary brain calcification: an international study reporting novel variants and associated phenotypes
- Author
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Ramos, Eliana Marisa, Carecchio, Miryam, Lemos, Roberta, Ferreira, Joana, Legati, Andrea, Sears, Renee Louise, Hsu, Sandy Chan, Panteghini, Celeste, Magistrelli, Luca, Salsano, Ettore, Esposito, Silvia, Taroni, Franco, Richard, Anne-Claire, Tranchant, Christine, Anheim, Mathieu, Ayrignac, Xavier, Goizet, Cyril, Vidailhet, Marie, Maltete, David, Wallon, David, Frebourg, Thierry, Pimentel, Lylyan, Geschwind, Daniel H, Vanakker, Olivier, Galasko, Douglas, Fogel, Brent L, Innes, A Micheil, Ross, Alison, Dobyns, William B, Alcantara, Diana, O'Driscoll, Mark, Hannequin, Didier, Campion, Dominique, French PFBC study group, Oliveira, João R, Garavaglia, Barbara, Coppola, Giovanni, Nicolas, Gaël, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Universidade Federal de Pernambuco [Recife] (UFPE), Interdisciplinary Institute for Neuroscience (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università del Piemonte Orientale - Dipartimento DISIT Italy, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Center for Medical Genetics [Ghent], Ghent University Hospital, University of California [San Diego] (UC San Diego), University of California, University of Calgary, Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK, Center for Integrative Brain Research, University of Washington [Seattle], Tecnológico de Monterrey (ITESM), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), and UNIROUEN - UFR Santé (UNIROUEN UFR Santé)
- Subjects
0301 basic medicine ,Proband ,Male ,Adolescent ,Adult ,Aged ,Aged, 80 and over ,Brain Diseases ,Calcinosis ,Child ,Cognitive Dysfunction ,Female ,Genetic Variation ,Heterozygote ,Humans ,Middle Aged ,Mutation ,Pedigree ,Phenotype ,Proto-Oncogene Proteins c-sis ,Receptor, Platelet-Derived Growth Factor beta ,Receptors, G-Protein-Coupled ,Receptors, Virus ,Sodium-Phosphate Cotransporter Proteins, Type III ,Young Adult ,QP0551 ,[SDV]Life Sciences [q-bio] ,RB024 ,Type III ,INORGANIC-PHOSPHATE ,0302 clinical medicine ,Receptors ,Medicine and Health Sciences ,80 and over ,2.1 Biological and endogenous factors ,HETEROGENEITY ,Family history ,Aetiology ,Genetics (clinical) ,Genetics & Heredity ,PDGFB ,French PFBC study group ,Parkinsonism ,Platelet-Derived Growth Factor beta ,3. Good health ,Virus ,Mental Health ,Neurological ,Medical genetics ,QP0624 ,SLC20A2 MUTATIONS ,Receptor ,medicine.medical_specialty ,Genetic counseling ,Clinical Sciences ,PDGFRB ,and over ,MAJOR CAUSE ,RB127 ,Article ,03 medical and health sciences ,G-Protein-Coupled ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,INFANTILE MYOFIBROMATOSIS ,Genetics ,Genetic Testing ,SPECTRUM ,business.industry ,Neurosciences ,Biology and Life Sciences ,Sodium-Phosphate Cotransporter Proteins ,QP0361 ,medicine.disease ,BASAL GANGLIA CALCIFICATION ,PDGFRB MUTATION ,GENE ,Brain Disorders ,030104 developmental biology ,business ,Xenotropic and Polytropic Retrovirus Receptor ,030217 neurology & neurosurgery ,Calcification - Abstract
International audience; Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
- Published
- 2018