TY - JOUR
T1 - Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification
AU - Hsu, Sandy Chan
AU - Sears, Renee L.
AU - Lemos, Roberta R.
AU - Quintáns, Beatriz
AU - Huang, Alden
AU - Spiteri, Elizabeth
AU - Nevarez, Lisette
AU - Mamah, Catherine
AU - Zatz, Mayana
AU - Pierce, Kerrie D.
AU - Fullerton, Janice M.
AU - Adair, John C.
AU - Berner, Jon E.
AU - Bower, Matthew
AU - Brodaty, Henry
AU - Carmona, Olga
AU - Dobricić, Valerija
AU - Fogel, Brent L.
AU - García-Estevez, Daniel
AU - Goldman, Jill
AU - Goudreau, John L.
AU - Hopfer, Suellen
AU - Janković, Milena
AU - Jaumà, Serge
AU - Jen, Joanna C.
AU - Kirdlarp, Suppachok
AU - Klepper, Joerg
AU - Kostić, Vladimir
AU - Lang, Anthony E.
AU - Linglart, Agnès
AU - Maisenbacher, Melissa K.
AU - Manyam, Bala V.
AU - Mazzoni, Pietro
AU - Miedzybrodzka, Zofia
AU - Mitarnun, Witoon
AU - Mitchell, Philip B.
AU - Mueller, Jennifer
AU - Novaković, Ivana
AU - Paucar, Martin
AU - Paulson, Henry
AU - Simpson, Sheila A.
AU - Svenningsson, Per
AU - Tuite, Paul
AU - Vitek, Jerrold
AU - Wetchaphanphesat, Suppachok
AU - Williams, Charles
AU - Yang, Michele
AU - Schofield, Peter R.
AU - De Oliveira, João R M
AU - Sobrido, María Jesús
AU - Geschwind, Daniel H.
AU - Coppola, Giovanni
N1 - Funding Information:
We would like to acknowledge and thank all of the participants and families for their valuable contribution to our study. This work was funded by NIH/NINDS (R01 NS040752 to DHG), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico to JRMO and MZ), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior to JRMO), FAPESP/CEPID (State of São Paulo Research Foundation to MZ), FACEPE (Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco to JRMO), Australian NHMRC (program grant 510135 to PBM), Ministry of Education and Science, Republic of Serbia (grant no. 175090 to VK, MJ, VD, and IN), and NIMH (K08 MH86297 to BLF). MJS and BQ are supported by research contracts from the Institute of Health Carlos III, European Regional Development Funds (FEDER) and the Botin Foundation. JG is supported by NIH (PSO AG008702-22 to M. Shelanski).
PY - 2013/2
Y1 - 2013/2
N2 - Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
AB - Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
KW - Basal ganglia calcification
KW - Fahr's
KW - Genetics
KW - Mutations
KW - Sequencing
UR - http://www.scopus.com/inward/record.url?scp=84873738898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873738898&partnerID=8YFLogxK
U2 - 10.1007/s10048-012-0349-2
DO - 10.1007/s10048-012-0349-2
M3 - Article
C2 - 23334463
AN - SCOPUS:84873738898
SN - 1364-6745
VL - 14
SP - 11
EP - 22
JO - Neurogenetics
JF - Neurogenetics
IS - 1
ER -