title: Whole exome sequencing and the clinician: we need clinical skills and functional validation in variant filtering.
abstract: Whole exome sequencing (WES) is a recently developed technique in genetics research that attempts to identify causative mutations in complex, undiagnosed genetic conditions. Causative mutations are usually identified after filtering the hundreds of variants on WES from an individual's DNA selected by the phenotype. We investigated a patient with a slowly progressive chronic axonal distal motor neuropathy and extrapyramidal syndrome using WES, in whom common genetic mutations had been excluded. Variant filtering identified potentially deleterious mutations in three known disease genes: DCTN1, KIF5A and NEFH, which have been all associated with similar clinical presentations of amyotrophic lateral sclerosis, Parkinsonism and/or hereditary spastic paraplegia. Predicting the functional effect of the mutations were analysed in parallel with detailed clinical investigations. This case highlights the difficulties and pitfalls of applying WES in patients with complex neurological diseases and serves as an instructive tale.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK, dbdaud@gmail.com.
authors.forename: Daniyal
authors.initials: D
authors.lastname: Daud
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Douroudis
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kleinle
authors.forename: Gail
authors.initials: G
authors.lastname: Eglon
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000368:Aged; D001416:Back Pain / Q000150:complications; D001480:Basal Ganglia Diseases / Q000150:complications* / Q000235:genetics*; D018450:Disease Progression; D000072159:Dynactin Complex; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009069:Movement Disorders / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics; D012585:Sciatica / Q000150:complications / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; C500506:KIF5A protein, human; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D016547:Kinesins