Primary brain calcification: an international study reporting novel variants and associated phenotypes.

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, The French PBC Study group, , Oliveira, João R, Garavaglia, Barbara, Coppola, Giovanni and Nicolas, Gaël (2018) Primary brain calcification: an international study reporting novel variants and associated phenotypes. European Journal of Human Genetics, 26 (10). pp. 1462-1477. ISSN 1018-4813

[img] PDF - Accepted Version
Download (287kB)

Abstract

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Global Health and Infection
School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system
Q Science > QP Physiology > QP0501 Animal biochemistry > QP0551 Proteins, amino acids, etc.
Q Science > QP Physiology > QP0501 Animal biochemistry > QP0620 Nucleic acids > QP0624 Deoxyribonucleic acids
R Medicine > RB Pathology > RB024 Pathological anatomy and histology
R Medicine > RB Pathology > RB127 Manifestations of disease
Related URLs:
Depositing User: Mark O'Driscoll
Date Deposited: 03 Jul 2018 08:39
Last Modified: 16 Jul 2019 14:15
URI: http://sro.sussex.ac.uk/id/eprint/76857

View download statistics for this item

📧 Request an update