Now including more than 20 research groups, the ASC has as its goal to collectively exploit sequencing approaches to resolve a substantial fraction of the genetic factors involved in ASD. While there are probably many hundreds of undiscovered

ASD loci, emerging data provide sufficient empirical evidence upon which to develop Decitabine cost sound and systematic approaches to identifying these loci. From the outset, the effort to constitute the group and define the objectives for the ASC was faced with the challenge of balancing the obvious benefits of working cooperatively with the strongly held conviction that a diversity of approaches and the presence of multiple competing efforts has played, and will continue to play, an indispensable role in the field’s rapid progress. The participating investigators undertook an effort to selleck chemicals llc address the range of related issues, including data sharing, prospectively and prior to the widespread availability of HTS data. In 2011, the ASC held an open meeting of investigators, funders, and other stakeholders to refine and crystallize the plans and proposals. The meeting,

which included more than 100 onsite participants (see Table S1 available online) and additional web participants, was organized around three working groups: (1) sequence technology, data harmonization, and statistical inference (B. Devlin and M. Daly, Chairs); (2) samples and phenotypes (J. Buxbaum and M. Gill, Chairs); and (3) future directions (T. Lehner and M. State, Chairs). Working groups addressed a variety of issues including study designs, statistical approaches,

sample availability and composition, data normalization, bioinformatics challenges, and the integration of gene discovery into broader efforts at translational neuroscience (Table S2). The meeting was video cast and can be accessed at http://videocast.nih.gov/pastevents.asp. We present a synthesis and summary of that meeting, reflecting both a current view of the field and consensus recommendations for gene discovery. In light of the high degree of genetic heterogeneity in ASD, it was apparent those that HTS would provide a powerful platform for gene discovery. Whole-genome sequencing (WGS) can detect structural variation of all types, ranging from gross chromosomal rearrangements to CNV and insertion deletions (indels), while also providing highly sensitive single-base resolution. Similarly, whole-exome sequencing (WES) can reliably detect single-nucleotide variants (SNVs) in the coding segments of the genome, many indels, and some CNV. Of course, both technologies provide the ability to identify rare alleles to a degree that is not possible on genotyping platforms. To date, four large-scale ASD WES studies have been carried out in trios, namely a proband with ASD and the biological parents, or in quads, a trio plus an unaffected sibling (Iossifov et al.