Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Sandy Chan Hsu, Renee L. Sears, Roberta R. Lemos, Beatriz Quintáns, Alden Huang, Elizabeth Spiteri, Lisette Nevarez, Catherine Mamah, Mayana Zatz, Kerrie D. Pierce, Janice M. Fullerton, John C. Adair, Jon E. Berner, Matthew Bower, Henry Brodaty, Olga Carmona, Valerija Dobricić, Brent L. Fogel, Daniel García-Estevez, Jill GoldmanJohn L. Goudreau, Suellen Hopfer, Milena Janković, Serge Jaumà, Joanna C. Jen, Suppachok Kirdlarp, Joerg Klepper, Vladimir Kostić, Anthony E. Lang, Agnès Linglart, Melissa K. Maisenbacher, Bala V. Manyam, Pietro Mazzoni, Zofia Miedzybrodzka, Witoon Mitarnun, Philip B. Mitchell, Jennifer Mueller, Ivana Novaković, Martin Paucar, Henry Paulson, Sheila A. Simpson, Per Svenningsson, Paul Tuite, Jerrold Vitek, Suppachok Wetchaphanphesat, Charles Williams, Michele Yang, Peter R. Schofield, João R.M. De Oliveira, María Jesús Sobrido, Daniel H. Geschwind*, Giovanni Coppola

*Corresponding author for this work
105 Citations (Scopus)


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.

Original languageEnglish
Issue number1
Pages (from-to)11-22
Number of pages12
Publication statusPublished - 02.2013


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