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Reference: Reid, ES, Papandreou, A, Drury, S et al., (2016). Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes. Brain, 139 (11), 2844-2854.Citable link to this page:

 

Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes

Abstract: Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts.

Publication status:PublishedPeer Review status:Peer reviewedVersion:Publisher's versionDate of acceptance:14 July 2016 Funder: University College London   Funder: Great Ormond Street Hospital Children's Charity   Funder: National Institute for Health Research   Notes:Copyright © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Bibliographic Details

Publisher: Oxford University Press

Publisher Website: http://www.oxfordjournals.org/

Journal: Brainsee more from them

Publication Website: http://brain.oxfordjournals.org/

Volume: 139

Issue: 11

Extent: 2844-2854

Issue Date: 06 September 2016

pages:2844-2854Identifiers

Doi: https://doi.org/10.1093/brain/aww221

Eissn: 1460-2156

Issn: 0006-8950

Uuid: uuid:80f90bbf-0b53-44f7-ae94-07f981fd9648

Urn: uri:80f90bbf-0b53-44f7-ae94-07f981fd9648

Pubs-id: pubs:641982 Item Description

Type: journal-article;

Language: eng

Version: Publisher's versionKeywords: gene panel heterogeneity inborn errors of metabolism neurometabolic disorders next-generation sequencing

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Author: Reid, ES - - - Papandreou, A - - - Drury, S - - - Boustred, C - - - Yue, W - Oxford, MSD, NDM, Structural Genomics Consortium - -

Source: https://ora.ox.ac.uk/objects/uuid:80f90bbf-0b53-44f7-ae94-07f981fd9648



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