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Primary brain calcification: an international study reporting novel variants and associated phenotypes.
- Source :
-
European journal of human genetics : EJHG [Eur J Hum Genet] 2018 Oct; Vol. 26 (10), pp. 1462-1477. Date of Electronic Publication: 2018 Jun 28. - Publication Year :
- 2018
-
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 (nā=ā34, 19.2%) or VUS (nā=ā11, 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.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Brain Diseases physiopathology
Calcinosis physiopathology
Child
Cognitive Dysfunction physiopathology
Female
Heterozygote
Humans
Male
Middle Aged
Mutation genetics
Pedigree
Phenotype
Proto-Oncogene Proteins c-sis genetics
Receptor, Platelet-Derived Growth Factor beta genetics
Receptors, G-Protein-Coupled drug effects
Receptors, Virus drug effects
Sodium-Phosphate Cotransporter Proteins, Type III genetics
Xenotropic and Polytropic Retrovirus Receptor
Young Adult
Brain Diseases genetics
Calcinosis genetics
Cognitive Dysfunction genetics
Genetic Variation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5438
- Volume :
- 26
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- European journal of human genetics : EJHG
- Publication Type :
- Academic Journal
- Accession number :
- 29955172
- Full Text :
- https://doi.org/10.1038/s41431-018-0185-4