De novo point mutations in patients diagnosed with ataxic cerebral palsy

R. Parolin Schnekenberg, E.M. Perkins, J.W. Miller, Wayne Davies, M.C. D'Adamo, M. Pessia, K.A. Fawcett, D. Sims, E. Gillard, K. Hudspith, P. Skehel, J. Williams, M. O'Regan, S. Jayawant, R. Jefferson, S. Hughes, A. Lustenberger, J. Ragoussis, M. Jackson, S.J. Tucker & 1 others A.H. Németh

    Research output: Contribution to journalArticle

    59 Citations (Scopus)

    Abstract

    © 2015 The Author. Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.
    Original languageEnglish
    Pages (from-to)1817-1832
    JournalBrain
    Volume138
    Issue number7
    Early online date16 May 2015
    DOIs
    Publication statusPublished - Jul 2015

    Fingerprint

    Cerebral Palsy
    Point Mutation
    Mutation
    Asphyxia
    Paternal Age
    Exome
    Ataxia
    Computational Biology
    Causality
    Parturition
    Cerebral Palsy, Ataxic, Autosomal Recessive
    Genes

    Cite this

    Parolin Schnekenberg, R., Perkins, E. M., Miller, J. W., Davies, W., D'Adamo, M. C., Pessia, M., ... Németh, A. H. (2015). De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain, 138(7), 1817-1832. https://doi.org/10.1093/brain/awv117
    Parolin Schnekenberg, R. ; Perkins, E.M. ; Miller, J.W. ; Davies, Wayne ; D'Adamo, M.C. ; Pessia, M. ; Fawcett, K.A. ; Sims, D. ; Gillard, E. ; Hudspith, K. ; Skehel, P. ; Williams, J. ; O'Regan, M. ; Jayawant, S. ; Jefferson, R. ; Hughes, S. ; Lustenberger, A. ; Ragoussis, J. ; Jackson, M. ; Tucker, S.J. ; Németh, A.H. / De novo point mutations in patients diagnosed with ataxic cerebral palsy. In: Brain. 2015 ; Vol. 138, No. 7. pp. 1817-1832.
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    title = "De novo point mutations in patients diagnosed with ataxic cerebral palsy",
    abstract = "{\circledC} 2015 The Author. Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.",
    author = "{Parolin Schnekenberg}, R. and E.M. Perkins and J.W. Miller and Wayne Davies and M.C. D'Adamo and M. Pessia and K.A. Fawcett and D. Sims and E. Gillard and K. Hudspith and P. Skehel and J. Williams and M. O'Regan and S. Jayawant and R. Jefferson and S. Hughes and A. Lustenberger and J. Ragoussis and M. Jackson and S.J. Tucker and A.H. N{\'e}meth",
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    Parolin Schnekenberg, R, Perkins, EM, Miller, JW, Davies, W, D'Adamo, MC, Pessia, M, Fawcett, KA, Sims, D, Gillard, E, Hudspith, K, Skehel, P, Williams, J, O'Regan, M, Jayawant, S, Jefferson, R, Hughes, S, Lustenberger, A, Ragoussis, J, Jackson, M, Tucker, SJ & Németh, AH 2015, 'De novo point mutations in patients diagnosed with ataxic cerebral palsy' Brain, vol. 138, no. 7, pp. 1817-1832. https://doi.org/10.1093/brain/awv117

    De novo point mutations in patients diagnosed with ataxic cerebral palsy. / Parolin Schnekenberg, R.; Perkins, E.M.; Miller, J.W.; Davies, Wayne; D'Adamo, M.C.; Pessia, M.; Fawcett, K.A.; Sims, D.; Gillard, E.; Hudspith, K.; Skehel, P.; Williams, J.; O'Regan, M.; Jayawant, S.; Jefferson, R.; Hughes, S.; Lustenberger, A.; Ragoussis, J.; Jackson, M.; Tucker, S.J.; Németh, A.H.

    In: Brain, Vol. 138, No. 7, 07.2015, p. 1817-1832.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - De novo point mutations in patients diagnosed with ataxic cerebral palsy

    AU - Parolin Schnekenberg, R.

    AU - Perkins, E.M.

    AU - Miller, J.W.

    AU - Davies, Wayne

    AU - D'Adamo, M.C.

    AU - Pessia, M.

    AU - Fawcett, K.A.

    AU - Sims, D.

    AU - Gillard, E.

    AU - Hudspith, K.

    AU - Skehel, P.

    AU - Williams, J.

    AU - O'Regan, M.

    AU - Jayawant, S.

    AU - Jefferson, R.

    AU - Hughes, S.

    AU - Lustenberger, A.

    AU - Ragoussis, J.

    AU - Jackson, M.

    AU - Tucker, S.J.

    AU - Németh, A.H.

    PY - 2015/7

    Y1 - 2015/7

    N2 - © 2015 The Author. Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.

    AB - © 2015 The Author. Cerebral palsy is a sporadic disorder with multiple likely aetiologies, but frequently considered to be caused by birth asphyxia. Genetic investigations are rarely performed in patients with cerebral palsy and there is little proven evidence of genetic causes. As part of a large project investigating children with ataxia, we identified four patients in our cohort with a diagnosis of ataxic cerebral palsy. They were investigated using either targeted next generation sequencing or trio-based exome sequencing and were found to have mutations in three different genes, KCNC3, ITPR1 and SPTBN2. All the mutations were de novo and associated with increased paternal age. The mutations were shown to be pathogenic using a combination of bioinformatics analysis and in vitro model systems. This work is the first to report that the ataxic subtype of cerebral palsy can be caused by de novo dominant point mutations, which explains the sporadic nature of these cases. We conclude that at least some subtypes of cerebral palsy may be caused by de novo genetic mutations and patients with a clinical diagnosis of cerebral palsy should be genetically investigated before causation is ascribed to perinatal asphyxia or other aetiologies.

    U2 - 10.1093/brain/awv117

    DO - 10.1093/brain/awv117

    M3 - Article

    VL - 138

    SP - 1817

    EP - 1832

    JO - Brain: a journal of neurology

    JF - Brain: a journal of neurology

    SN - 0006-8950

    IS - 7

    ER -

    Parolin Schnekenberg R, Perkins EM, Miller JW, Davies W, D'Adamo MC, Pessia M et al. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain. 2015 Jul;138(7):1817-1832. https://doi.org/10.1093/brain/awv117