As the number of trios or quads sequenced grows linearly, the rate of gene identification is predicted to accelerate (Figure 1). Based on the first results from the ASC sites, the value of expanding efforts in search of recurrent de novo events is clear. If HTS were to be performed on 8,000 families, and even ignoring other sources of key information, the experiment should yield between 40–60 novel ASD genes and a large number of additional genes falling just short of significance that could readily be confirmed via targeted sequencing in

additional large patient cohorts (Figure 1). Efforts of this scale are underway. To give some examples, the Simons Foundation has committed to sequencing more than 2,600 quartets, the ARRA Autism Sequencing Consortium has finished 400 families, Genome Canada is supporting this website the sequencing of 1,000 trios and families, and the UK10K project is targeting ∼800 ASD cases in the 10,000 to be sequenced. Autism Speaks, in partnership with the Beijing Genomics Institute, is committed to whole-genome sequencing of 60 families and has proposed an ultimate target of 2,000 families. A key related question is whether an even higher yield of ASD genes can be gleaned simply by making more effective use of data generated in ongoing experiments. In fact, it is a near certainty that there will be significant traction in evaluating

other types of mutations beyond de novo LoF variants. Ongoing Ulixertinib ic50 research promises to refine the interpretation of various classes of mutations, including inherited variation from family and case-control analyses, for which the chief obstacle is the high frequency of apparently neutral rare variation in the genome. In addition, there are already emerging successes focusing on recessive and X-linked

LoF variation. These efforts may be aided through the study of sequence data in unusual high-risk extended pedigrees that are also available. Thus, based on refined interpretation of sequence, we expect to identify additional ASD genes. Progress in this area will also require methods to combine data on inherited variation with data on de novo events. The ASC recognizes most that a focus on DNA sequence, by itself, is insufficient. There are additional sources of information that can be brought to bear to identify novel ASD genes (Figure 2). RNA-seq and Chip-seq studies of typical and ASD brains offer an increasingly accurate picture of gene coexpression and regulatory networks, thereby identifying processes altered in ASD, both by themselves and by overlap with genes identified as disrupted in ASD. And RNA-seq studies of peripheral samples (blood or induced neural cells) have the potential to survey thousands of individuals to identify ASD-related biological signatures.