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

doi:10.1212/NXG.0000000000000187

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)

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

222 Downloads (Pure)

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 language	English
Article number	e187
Pages (from-to)	1-6
Number of pages	6
Journal	Neurology Genetics
Volume	3
Issue number	5
Early online date	22 Sept 2017
DOIs	https://doi.org/10.1212/NXG.0000000000000187
Publication status	Published - Oct 2017

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10.1212/NXG.0000000000000187Licence: CC BY

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© 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 390 KBLicence: CC BY

Cite this

@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. ",

year = "2017",

month = oct,

doi = "10.1212/NXG.0000000000000187",

language = "English",

volume = "3",

pages = "1--6",

journal = "Neurology Genetics",

issn = "2376-7839",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

TY - JOUR

T1 - De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

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.

U2 - 10.1212/NXG.0000000000000187

DO - 10.1212/NXG.0000000000000187

M3 - Article

C2 - 28955726

SN - 2376-7839

VL - 3

SP - 1

EP - 6

JO - Neurology Genetics

JF - Neurology Genetics

IS - 5

M1 - e187

ER -

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

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