De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

Ewen W. Sommerville, Charlotte L. Alston, Angela Pyle, Langping He, Gavin Falkous, Karen Naismith, Patrick F. Chinnery, Robert McFarland, Robert W. Taylor (Lead / Corresponding author)

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    Abstract

    Objective: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.

    Methods: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.

    Results: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.

    Conclusions: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

    Original languageEnglish
    Article numbere187
    Pages (from-to)1-6
    Number of pages6
    JournalNeurology Genetics
    Volume3
    Issue number5
    Early online date22 Sep 2017
    DOIs
    Publication statusPublished - Oct 2017

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    Mitochondrial Diseases
    Electron Transport
    Exome
    Neurodegenerative Diseases
    Skeletal Muscle

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    Sommerville, E. W., Alston, C. L., Pyle, A., He, L., Falkous, G., Naismith, K., ... Taylor, R. W. (2017). De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities. Neurology Genetics, 3(5), 1-6. [e187]. https://doi.org/10.1212/NXG.0000000000000187
    Sommerville, Ewen W. ; Alston, Charlotte L. ; Pyle, Angela ; He, Langping ; Falkous, Gavin ; Naismith, Karen ; Chinnery, Patrick F. ; McFarland, Robert ; Taylor, Robert W. / De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities. In: Neurology Genetics. 2017 ; Vol. 3, No. 5. pp. 1-6.
    @article{95ff9990c35b46dab282f544cf386d9e,
    title = "De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities",
    abstract = "Objective: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.",
    author = "Sommerville, {Ewen W.} and Alston, {Charlotte L.} and Angela Pyle and Langping He and Gavin Falkous and Karen Naismith and Chinnery, {Patrick F.} and Robert McFarland and Taylor, {Robert W.}",
    note = "E.W. Sommerville reports no disclosures. C.L. Alston is supported by the National Institute for Health Research (NIHR) doctoral fellowship (NIHR-HCS-D12-03-04). A. Pyle, L. He, G. Falkous, and K. Naismith report no disclosures. P.F. Chinnery has served on the editorial board of BRAIN; in addition, he is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). R. McFarland has served on the scientific advisory boards of the United Mitochondrial Disease Foundation and the Lily Foundation and receives research support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the Ryan Stanford Appeal, and the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service. R.W. Taylor receives research support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust. Go to Neurology.org/ng for full disclosure forms.",
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    Sommerville, EW, Alston, CL, Pyle, A, He, L, Falkous, G, Naismith, K, Chinnery, PF, McFarland, R & Taylor, RW 2017, 'De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities', Neurology Genetics, vol. 3, no. 5, e187, pp. 1-6. https://doi.org/10.1212/NXG.0000000000000187

    De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities. / Sommerville, Ewen W.; Alston, Charlotte L.; Pyle, Angela; He, Langping; Falkous, Gavin; Naismith, Karen; Chinnery, Patrick F.; McFarland, Robert; Taylor, Robert W. (Lead / Corresponding author).

    In: Neurology Genetics, Vol. 3, No. 5, e187, 10.2017, p. 1-6.

    Research output: Contribution to journalArticle

    TY - JOUR

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    AU - Sommerville, Ewen W.

    AU - Alston, Charlotte L.

    AU - Pyle, Angela

    AU - He, Langping

    AU - Falkous, Gavin

    AU - Naismith, Karen

    AU - Chinnery, Patrick F.

    AU - McFarland, Robert

    AU - Taylor, Robert W.

    N1 - E.W. Sommerville reports no disclosures. C.L. Alston is supported by the National Institute for Health Research (NIHR) doctoral fellowship (NIHR-HCS-D12-03-04). A. Pyle, L. He, G. Falkous, and K. Naismith report no disclosures. P.F. Chinnery has served on the editorial board of BRAIN; in addition, he is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2). R. McFarland has served on the scientific advisory boards of the United Mitochondrial Disease Foundation and the Lily Foundation and receives research support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the Ryan Stanford Appeal, and the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service. R.W. Taylor receives research support from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust. Go to Neurology.org/ng for full disclosure forms.

    PY - 2017/10

    Y1 - 2017/10

    N2 - Objective: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

    AB - Objective: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results: After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.

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    DO - 10.1212/NXG.0000000000000187

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    JO - Neurology Genetics

    JF - Neurology Genetics

    SN - 2376-7839

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