title: Exome sequencing can detect pathogenic mosaic mutations present at low allele frequencies.
abstract: The development of next generation sequencing (NGS) has radically transformed the scientific landscape, making it possible to sequence the exome of any given individual in a cost-effective way. The power of this approach has been demonstrated by a number of groups who have identified pathogenic mutations in small pedigrees that have been resistant to traditional genetic mapping. Recently it has become clear that exome sequencing has great potential with respect to sporadic disease and the identification of de novo mutations. This is highlighted by studies reporting whole-exome sequencing of patient-parental trios affected by learning disability, autism and schizophrenia. It is widely anticipated that the introduction of this technique into a clinical setting will revolutionise genetic diagnosis. However, the sensitivity of NGS exome sequencing is currently unclear. Here, we describe the exome sequencing of DNA samples from a patient with double cortex syndrome and her parents, resulting in the detection of a mosaic splicing mutation in LIS1. This variant was found at an allele frequency of just 18%, demonstrating that NGS methods have the capacity to identify pathogenic mosaic mutations present at a low level.
authors: NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors: Alistair T
authors: AT
authors: Pagnamenta
authors: Stefano
authors: S
authors: Lise
authors: Victoria
authors: V
authors: Harrison
authors: Helen
authors: H
authors: Stewart
authors: Sandeep
authors: S
authors: Jayawant
authors: Gerardine
authors: G
authors: Quaghebeur
authors: Alexander T
authors: AT
authors: Deng
authors: Valerie Elizabeth
authors: VE
authors: Murphy
authors: Elham
authors: E
authors: Sadighi Akha
authors: Andy
authors: A
authors: Rimmer
authors: Iain
authors: I
authors: Mathieson
authors: Samantha J L
authors: SJ
authors: Knight
authors: Usha
authors: U
authors: Kini
authors: Jenny C
authors: JC
authors: Taylor
authors: David A
authors: DA
authors: Keays
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D009030:Mosaicism; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human