title: Characterisation and validation of insertions and deletions in 173 patient exomes.
abstract: Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.
authors.affiliation: UCL Genomics, University College London, London, United Kingdom. f.lescai@ucl.ac.uk
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonfiglio
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.forename: Aoife
authors.initials: A
authors.lastname: Waters
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.forename: Dalia
authors.initials: D
authors.lastname: Kasperavičiūtė
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: John
authors.initials: J
authors.lastname: Anderson
authors.forename: David
authors.initials: D
authors.lastname: Kelsell
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wood
authors.forename: Una
authors.initials: U
authors.lastname: Sheerin
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Donna
authors.initials: D
authors.lastname: Mackay
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Jane
authors.initials: J
authors.lastname: Sowden
authors.forename: Veronica
authors.initials: V
authors.lastname: Kinsler
authors.forename: Justyna
authors.initials: J
authors.lastname: Osinska
authors.forename: Tony
authors.initials: T
authors.lastname: Brooks
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.forename: Philip
authors.initials: P
authors.lastname: Beales
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
mesh_terms: D059472:Exome; D006801:Humans; D016254:Mutagenesis, Insertional; D017384:Sequence Deletion