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

Sandy Chan Hsu, Renee L. Sears, Roberta R. Lemos, Beatriz Quintans, 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 Dobricic, Brent L. Fogel, Daniel Garcia-Estevez, Jill Goldman & 32 others John L. Goudreau, Suellen Hopfer, Milena Jankovic, Serge Jauma, Joanna C. Jen, Suppachok Kirdlarp, Joerg Klepper, Vladimir Kostic, Anthony E. Lang, Agnes Linglart, Melissa K. Maisenbacher, Bala V. Manyam, Pietro Mazzoni, Zofia Miedzybrodzka, Witoon Mitarnun, Philip B. Mitchell, Jennifer Mueller, Ivana Novakovic, Martin Paucar, Henry Paulson, Sheila A. Simpson, Per Svenningsson, Paul Tuite, Jerrold Vitek, Suppachok Wetchaphanphesat, Charles Williams, Michele Yang, Peter R. Schofield, Joao R. M. de Oliveira, Maria-Jesus Sobrido, Daniel H. Geschwind, Giovanni Coppola

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11-22
Number of pages12
JournalNeurogenetics
Volume14
Issue number1
Early online date20 Jan 2013
DOIs
Publication statusPublished - Feb 2013

Keywords

  • Basal ganglia calcification
  • Fahr's
  • Genetics
  • Sequencing
  • Mutations
  • Chromosome 14Q
  • Fahr-Disease
  • Locus
  • Identification
  • 8P21.1-Q11.23
  • Tomography

Cite this

Hsu, S. C., Sears, R. L., Lemos, R. R., Quintans, B., Huang, A., Spiteri, E., ... Coppola, G. (2013). Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics, 14(1), 11-22. https://doi.org/10.1007/s10048-012-0349-2

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. / Hsu, Sandy Chan; Sears, Renee L.; Lemos, Roberta R.; Quintans, Beatriz; Huang, Alden; Spiteri, Elizabeth; Nevarez, Lisette; Mamah, Catherine; Zatz, Mayana; Pierce, Kerrie D.; Fullerton, Janice M.; Adair, John C.; Berner, Jon E.; Bower, Matthew; Brodaty, Henry; Carmona, Olga; Dobricic, Valerija; Fogel, Brent L.; Garcia-Estevez, Daniel; Goldman, Jill; Goudreau, John L.; Hopfer, Suellen; Jankovic, Milena; Jauma, Serge; Jen, Joanna C.; Kirdlarp, Suppachok; Klepper, Joerg; Kostic, Vladimir; Lang, Anthony E.; Linglart, Agnes; Maisenbacher, Melissa K.; Manyam, Bala V.; Mazzoni, Pietro; Miedzybrodzka, Zofia; Mitarnun, Witoon; Mitchell, Philip B.; Mueller, Jennifer; Novakovic, Ivana; Paucar, Martin; Paulson, Henry; Simpson, Sheila A.; Svenningsson, Per; Tuite, Paul; Vitek, Jerrold; Wetchaphanphesat, Suppachok; Williams, Charles; Yang, Michele; Schofield, Peter R.; de Oliveira, Joao R. M.; Sobrido, Maria-Jesus; Geschwind, Daniel H.; Coppola, Giovanni.

In: Neurogenetics, Vol. 14, No. 1, 02.2013, p. 11-22.

Research output: Contribution to journalArticle

Hsu, SC, Sears, RL, Lemos, RR, Quintans, B, Huang, A, Spiteri, E, Nevarez, L, Mamah, C, Zatz, M, Pierce, KD, Fullerton, JM, Adair, JC, Berner, JE, Bower, M, Brodaty, H, Carmona, O, Dobricic, V, Fogel, BL, Garcia-Estevez, D, Goldman, J, Goudreau, JL, Hopfer, S, Jankovic, M, Jauma, S, Jen, JC, Kirdlarp, S, Klepper, J, Kostic, V, Lang, AE, Linglart, A, Maisenbacher, MK, Manyam, BV, Mazzoni, P, Miedzybrodzka, Z, Mitarnun, W, Mitchell, PB, Mueller, J, Novakovic, I, Paucar, M, Paulson, H, Simpson, SA, Svenningsson, P, Tuite, P, Vitek, J, Wetchaphanphesat, S, Williams, C, Yang, M, Schofield, PR, de Oliveira, JRM, Sobrido, M-J, Geschwind, DH & Coppola, G 2013, 'Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification' Neurogenetics, vol. 14, no. 1, pp. 11-22. https://doi.org/10.1007/s10048-012-0349-2
Hsu, Sandy Chan ; Sears, Renee L. ; Lemos, Roberta R. ; Quintans, Beatriz ; Huang, Alden ; Spiteri, Elizabeth ; Nevarez, Lisette ; Mamah, Catherine ; Zatz, Mayana ; Pierce, Kerrie D. ; Fullerton, Janice M. ; Adair, John C. ; Berner, Jon E. ; Bower, Matthew ; Brodaty, Henry ; Carmona, Olga ; Dobricic, Valerija ; Fogel, Brent L. ; Garcia-Estevez, Daniel ; Goldman, Jill ; Goudreau, John L. ; Hopfer, Suellen ; Jankovic, Milena ; Jauma, Serge ; Jen, Joanna C. ; Kirdlarp, Suppachok ; Klepper, Joerg ; Kostic, Vladimir ; Lang, Anthony E. ; Linglart, Agnes ; Maisenbacher, Melissa K. ; Manyam, Bala V. ; Mazzoni, Pietro ; Miedzybrodzka, Zofia ; Mitarnun, Witoon ; Mitchell, Philip B. ; Mueller, Jennifer ; Novakovic, Ivana ; Paucar, Martin ; Paulson, Henry ; Simpson, Sheila A. ; Svenningsson, Per ; Tuite, Paul ; Vitek, Jerrold ; Wetchaphanphesat, Suppachok ; Williams, Charles ; Yang, Michele ; Schofield, Peter R. ; de Oliveira, Joao R. M. ; Sobrido, Maria-Jesus ; Geschwind, Daniel H. ; Coppola, Giovanni. / Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. In: Neurogenetics. 2013 ; Vol. 14, No. 1. pp. 11-22.
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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 - Quintans, 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 - Dobricic, Valerija

AU - Fogel, Brent L.

AU - Garcia-Estevez, Daniel

AU - Goldman, Jill

AU - Goudreau, John L.

AU - Hopfer, Suellen

AU - Jankovic, Milena

AU - Jauma, Serge

AU - Jen, Joanna C.

AU - Kirdlarp, Suppachok

AU - Klepper, Joerg

AU - Kostic, Vladimir

AU - Lang, Anthony E.

AU - Linglart, Agnes

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 - Novakovic, 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, Joao R. M.

AU - Sobrido, Maria-Jesus

AU - Geschwind, Daniel H.

AU - Coppola, Giovanni

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 - Sequencing

KW - Mutations

KW - Chromosome 14Q

KW - Fahr-Disease

KW - Locus

KW - Identification

KW - 8P21.1-Q11.23

KW - Tomography

U2 - 10.1007/s10048-012-0349-2

DO - 10.1007/s10048-012-0349-2

M3 - Article

VL - 14

SP - 11

EP - 22

JO - Neurogenetics

JF - Neurogenetics

SN - 1364-6745

IS - 1

ER -