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.

Fig. 1

Structure model of PiT2 protein with the variant locations. Red residues denote nonsense variants, orange residues denote missense variants, blue residues denote splice site variants, purple residues denote insertions/deletions, and green residues denote synonymous variants. ProDom domains (I11–L161 and V492–V640) are highlighted in gray

Fig. 2

DNA sequence chromatograms of the SLC20A2 variants identified in IBGC-affected families. Representative partial sequence chromatograms for family F1 (mutation: c.508delT) and F5 (p.Val195Leufs*61). The dark blue cursor denotes the position of the indicated mutation and the subsequent frameshift is shown with the blue and green highlighted bases

Fig. 3

Brain CT images of nonsegregating individuals and positive controls. a CT classified as positive for a F1 family member but tested negative for the variant; b CT-positive F1 family member with the variant showing abundant calcifications; c CT classified as positive for F5 family member at age 75 but tested negative for the variant; d CT-positive F5 family member with the variant showing abundant calcifications