title: The use of whole-exome sequencing to disentangle complex phenotypes.
abstract: The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine-Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked.
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Hywel J
authors.initials: HJ
authors.lastname: Williams
authors.affiliation: UCL Respiratory Medicine, UCL Medical School, London, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Hurst
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Chela
authors.initials: C
authors.lastname: James
authors.affiliation: Paediatric Respiratory Medicine, Royal London Hospital, Whitechapel, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pao
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.affiliation: UCL Respiratory Medicine, UCL Medical School, London, UK.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.|UCL Respiratory Medicine, UCL Medical School, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Department of Clinical Genetics, Great Ormond St Hospital, London, UK.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosser
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Centre for Translational Omics - GOSgene, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Beales
mesh_terms: D059472:Exome / Q000235:genetics*; D005260:Female; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C086745:periaxin