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Journal Articles European Journal of Human Genetics Year : 2018

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

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Xavier Ayrignac
Cyril Goizet
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  • PersonId : 925163
Marie Vidailhet
  • Function : Author
  • PersonId : 882724
Olivier Vanakker
  • Function : Author
  • PersonId : 937823
William Dobyns
  • Function : Author
  • PersonId : 908474
Diana Hernández Alcantara
  • Function : Author
  • PersonId : 1040103
Giovanni Coppola
  • Function : Author
  • PersonId : 977696

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.

Dates and versions

hal-02540078 , version 1 (10-04-2020)

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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, 2018, 26 (10), pp.1462-1477. ⟨10.1038/s41431-018-0185-4⟩. ⟨hal-02540078⟩
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