ABSTRACT
BACKGROUND: Linkage analyses of families with primary familial brain calcification (formerly idiopathic basal ganglia calcification [IBGC]) identified 3 candidate loci (IBGC1-3). Recently, SLC20A2 mutations were found in the IBGC1 and IBGC3 families, merging these 2 loci. We here elucidate the genetic cause of primary familial brain calcification in the 'IBGC2' kindred. METHODS: We sequenced known primary familial brain calcification genes and quantified SLC20A2 and PDGFB. Moreover, CT scans of affected and unaffected family members were evaluated by 2 blinded neuroradiologists for distribution of brain calcification. RESULTS: A heterozygous multiexonic SLC20A2 deletion was detected in several affected family members. A reevaluation of neuroimaging data revealed a subset of mutation-negative individuals with only mild and/or unilateral calcification. CONCLUSIONS: The identified SLC20A2 mutation resolves the genetic cause of primary familial brain calcification in the 'IBGC2' kindred, collapsing 'IBGC2' into IBGC1. We suggest an algorithm for predicting the chances of finding genetic mutations that has to be validated in further studies. Our study enhances criteria for the evaluation of neuroimaging data, contributing further to the much needed harmonization of diagnostic and research data collection in primary familial brain calcification. © 2016 International Parkinson and Movement Disorder Society.
Subject(s)
Basal Ganglia Diseases/diagnostic imaging , Basal Ganglia Diseases/genetics , Calcinosis/diagnostic imaging , Calcinosis/genetics , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/genetics , Sodium-Phosphate Cotransporter Proteins, Type III/genetics , Humans , Pedigree , Single-Blind MethodABSTRACT
Familial idiopathic basal ganglia calcification (FIBGC) is an inherited neurodegenerative disorder characterized by the accumulation of calcium deposits in different brain regions, particularly in the basal ganglia. FIBGC usually follows an autosomal dominant pattern of inheritance. Despite the mapping to chromosome 14q of a susceptibility locus for IBGC (IBCG1) in one family, this locus has been excluded in several others, demonstrating genetic heterogeneity in this disorder. The etiology of this disorder thus remains largely unknown. Using a large extended multigenerational Italian family from South Tyrol with 17 affected in a total of 56 members, we performed a genome-wide linkage analysis in which we were able to exclude linkage to the IBCG1 locus on chromosome 14q and obtain evidence of a novel locus on chromosome 2q37. Electronic supplementary material. The online version of this article (doi:10.1007/s12031-009-9287-3) contains supplementary material, which is available to authorized users.
Subject(s)
Basal Ganglia Diseases/genetics , Calcinosis/genetics , Chromosomes, Human, Pair 2/genetics , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Adult , Aged , Aged, 80 and over , Basal Ganglia/metabolism , Basal Ganglia/pathology , Basal Ganglia/physiopathology , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/physiopathology , Calcinosis/metabolism , Calcinosis/physiopathology , Chromosome Disorders/genetics , Chromosome Mapping , Chromosomes, Human, Pair 14/genetics , DNA Mutational Analysis , Female , Genes, Dominant/genetics , Genetic Linkage/genetics , Genetic Markers/genetics , Genetic Testing , Genetic Variation/genetics , Humans , Inheritance Patterns/genetics , Italy , Male , Middle Aged , PedigreeABSTRACT
Familial Idiopathic Basal Ganglia Calcification (FIBGC) is a neurodegenerative syndrome that usually follows an autosomal dominant pattern of inheritance. Linkage to only one locus on chromosome 14q (IBCG1) has been described so far. We identified and characterized a large multigenerational Italian family from a population isolate with 14 FIBGC affected members. Linkage analysis excluded the IBCG1 locus, thus demonstrating further locus heterogeneity for this disease.
