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

Eliana Marisa Ramos (1) , Miryam Carecchio (2) , Roberta Lemos (3) , Joana Ferreira (4, 3) , Andrea Legati (1) , Renee Louise Sears (1) , Sandy Chan Hsu (1) , Celeste Panteghini (2) , Luca Magistrelli (5) , Ettore Salsano (2) , Silvia Esposito (2) , Franco Taroni (2) , Anne-Claire Richard (6) , Christine Tranchant (7, 8) , Mathieu Anheim (7, 8) , Xavier Ayrignac (9) , Cyril Goizet (10) , Marie Vidailhet (11) , David Maltête (12) , David Wallon (13, 6) , Thierry Frebourg (6) , Lylyan Pimentel (3) , Daniel H. Geschwind (1) , Olivier Vanakker (14) , Douglas Galasko (15) , Brent L. Fogel (1) , a Micheil Innes (16) , Alison Ross (17) , William Dobyns (18) , Diana Hernández Alcantara (19) , Mark O’driscoll (19) , Didier Hannequin (13, 6) , Dominique Campion (20, 6) , João Oliveira (3) , Barbara Garavaglia (2) , Giovanni Coppola (21) , Gaël Nicolas (22, 6)

1 David Geffen School of Medicine [Los Angeles]
2 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
3 UFPE - Universidade Federal de Pernambuco [Recife]
4 IINS - Interdisciplinary Institute for Neuroscience
5 Università del Piemonte Orientale - Dipartimento DISIT Italy
6 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
7 FMTS - Fédération de Médecine Translationnelle de Strasbourg
8 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
9 INM - Institut des Neurosciences de Montpellier
10 Service de génétique médicale
11 ICM - Institut du Cerveau = Paris Brain Institute
12 ADEN - Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau
13 Service de neurologie [Rouen]
14 Center for Medical Genetics [Ghent]
15 UC San Diego - University of California [San Diego]
16 University of Calgary
17 Department of Clinical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK
18 Center for Integrative Brain Research
19 ITESM - Tecnológico de Monterrey
20 Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France
21 Università degli Studi di Salermo
22 UNIROUEN UFR Santé - UNIROUEN - UFR Santé

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.

Domains: Life Sciences [q-bio]

Eliana Marisa Ramos, Miryam Carecchio, Roberta Lemos, Joana Ferreira, Andrea Legati, et al.. Primary brain calcification: an international study reporting novel variants and associated phenotypes. European Journal of Human Genetics, 2018, 26 (10), pp.1462-1477. ⟨10.1038/s41431-018-0185-4⟩. ⟨hal-02540078⟩