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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 Geschwind 1 Olivier Vanakker 14 Douglas Galasko 15 Brent L. Fogel 1 a Micheil Innes 16 Alison Ross William Dobyns 17 Diana Alcantara 18 Mark O’driscoll 18 Didier Hannequin 13, 6 Dominique Campion 19, 6 João Oliveira 3 Barbara Garavaglia 2 Giovanni Coppola 20 Gaël Nicolas 21, 6
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.
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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, Nature Publishing Group, 2018, 26 (10), pp.1462-1477. ⟨10.1038/s41431-018-0185-4⟩. ⟨hal-02540078⟩

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