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PDGFR LoF Basal calcification. ACCEPTED MANUSCRIPT.pdf (280.95 kB)

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

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posted on 2023-06-09, 14:03 authored by Eliana Marisa Ramos, Miryam Carecchio, Roberta Lemos, Joana Ferreira, Andrea Legati, Renee Louise Sears, Sandy Chan Hsu, Celeste Panteghini, Luca Magistrelli, Ettore Salsano, Silvia Esposito, Franco Taroni, Anne-Claire Richard, Christine Tranchant, Mathieu Anheim, Xavier Ayrignac, Cyril Goizet, Marie Vidailhet, David Maltete, David Wallon, Thierry Frebourg, Lylyan Pimentel, Daniel H Geschwind, Olivier Vanakker, Douglas Galasko, Brent L Fogel, A Micheil Innes, Alison Ross, William B Dobyns, Diana AlcantaraDiana Alcantara, Mark O'DriscollMark O'Driscoll, Didier Hannequin, Dominique Campion, The French PBC Study group, João R Oliveira, Barbara Garavaglia, Giovanni Coppola, Gaël Nicolas
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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

European Journal of Human Genetics

ISSN

1018-4813

Publisher

Nature Publishing Group

Issue

10

Volume

26

Page range

1462-1477

Department affiliated with

  • Global Health and Infection Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-07-03

First Open Access (FOA) Date

2018-12-28

First Compliant Deposit (FCD) Date

2018-07-02

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