title: Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.
abstract: 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.
authors: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors: Sandy Chan
authors: SC
authors: Hsu
authors: Renee L
authors: RL
authors: Sears
authors: Roberta R
authors: RR
authors: Lemos
authors: Beatriz
authors: B
authors: Quintáns
authors: Alden
authors: A
authors: Huang
authors: Elizabeth
authors: E
authors: Spiteri
authors: Lisette
authors: L
authors: Nevarez
authors: Catherine
authors: C
authors: Mamah
authors: Mayana
authors: M
authors: Zatz
authors: Kerrie D
authors: KD
authors: Pierce
authors: Janice M
authors: JM
authors: Fullerton
authors: John C
authors: JC
authors: Adair
authors: Jon E
authors: JE
authors: Berner
authors: Matthew
authors: M
authors: Bower
authors: Henry
authors: H
authors: Brodaty
authors: Olga
authors: O
authors: Carmona
authors: Valerija
authors: V
authors: Dobricić
authors: Brent L
authors: BL
authors: Fogel
authors: Daniel
authors: D
authors: García-Estevez
authors: Jill
authors: J
authors: Goldman
authors: John L
authors: JL
authors: Goudreau
authors: Suellen
authors: S
authors: Hopfer
authors: Milena
authors: M
authors: Janković
authors: Serge
authors: S
authors: Jaumà
authors: Joanna C
authors: JC
authors: Jen
authors: Suppachok
authors: S
authors: Kirdlarp
authors: Joerg
authors: J
authors: Klepper
authors: Vladimir
authors: V
authors: Kostić
authors: Anthony E
authors: AE
authors: Lang
authors: Agnès
authors: A
authors: Linglart
authors: Melissa K
authors: MK
authors: Maisenbacher
authors: Bala V
authors: BV
authors: Manyam
authors: Pietro
authors: P
authors: Mazzoni
authors: Zofia
authors: Z
authors: Miedzybrodzka
authors: Witoon
authors: W
authors: Mitarnun
authors: Philip B
authors: PB
authors: Mitchell
authors: Jennifer
authors: J
authors: Mueller
authors: Ivana
authors: I
authors: Novaković
authors: Martin
authors: M
authors: Paucar
authors: Henry
authors: H
authors: Paulson
authors: Sheila A
authors: SA
authors: Simpson
authors: Per
authors: P
authors: Svenningsson
authors: Paul
authors: P
authors: Tuite
authors: Jerrold
authors: J
authors: Vitek
authors: Suppachok
authors: S
authors: Wetchaphanphesat
authors: Charles
authors: C
authors: Williams
authors: Michele
authors: M
authors: Yang
authors: Peter R
authors: PR
authors: Schofield
authors: João R M
authors: JR
authors: de Oliveira
authors: María-Jesús
authors: MJ
authors: Sobrido
authors: Daniel H
authors: DH
authors: Geschwind
authors: Giovanni
authors: G
authors: Coppola
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001480:Basal Ganglia Diseases / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000235:genetics*; D012189:Retrospective Studies; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics*
chemical_list: C493589:SLC20A2 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III