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

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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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Acknowledgements

We thank all the patients for participating in this study and the physicians who referred patients for the study. The coinvestigators of the French PFBC study group are listed in supplementary information.

Funding

This study was cosupported by CNR-MAJ, Inserm, European Union and Région Normandie. Europe gets involved in Normandie with European Regional Development Fund (ERDF) (French group). This study received support from FACEPE, CAPES, and CNPq (310150/2016-7,480255/2013-0, 440770/2016-5; IBPG-0627-2.02/11; IBPG-0162-2.02/14; BFP-0123-2.02/12; BR group). We acknowledge the support of the NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691), NIH grants R01 NS40752 to DHG, R01NS082094 to BLF, and R01 HL130996 to WBD, the Bev Carrick Memorial Fund to GC (US group), and Cancer Research UK Programme Award C24110/A15394 to MOD. Funding sources had no specific roles.

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Correspondence to Giovanni Coppola or Gaël Nicolas.

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