%0 Journal Article
%T Whole-exome sequencing for finding de novo mutations in sporadic mental retardation
%A Peter N Robinson
%J Genome Biology
%D 2010
%I BioMed Central
%R 10.1186/gb-2010-11-12-144
%X Sarah Ng and colleagues first showed that whole-exome sequencing (WES - sequencing of all the exons in the genome) can be used to identify disease genes in 2009 [1]. Clearly, WES represents a revolutionary technology. In light of the ever increasing number of novel disease genes that have been discovered with WES, it has almost come to seem routine, and in fact the first descriptions of applications of WES to make clinical decisions in the care of patients have begun to appear [2]. The article by Lisenka Vissers and colleagues in the December 2010 issue of Nature Genetics [3] demonstrates that the revolution is far from over. By providing convincing evidence that WES can be used to detect de novo mutations in patients with sporadic cases of non-syndromic mental retardation, the authors [3] have extended the range of clinical situations in which WES can be used and given suggestive evidence that de novo mutations are a common cause of mental retardation.One of the main challenges in WES is the sheer number of variants that are found in an exome. It is likely that each one of us - healthy or not - carries multiple sequence variants, such as nonsense mutations, that most geneticists would have assessed as disease-causing before whole-exome and whole-genome sequencing showed us how common such changes are in human genomes. The challenge in molecular genetic diagnostics is thus quickly shifting from the identification of sequence variants to the interpretation of the variants: which of the tens to hundreds of rare variants in an exome sequence with apparent pathogenic potential is the disease-causing mutation?Initial analysis strategies in exome sequencing sought to identify genes with rare, potentially pathogenic variants in all or most sequenced individuals with a given disease [1,4-6]. This approach, which we will call intersection filtering, narrows down the candidate set of genes by removing variants also found in databases of common polymorphisms such as dbSNP and
%U http://genomebiology.com/2010/11/12/144