Supplementary Materials Supplemental Material supp_1_1_a000422__index. of one affected kid, unaffected parents,

Supplementary Materials Supplemental Material supp_1_1_a000422__index. of one affected kid, unaffected parents, and one unaffected sibling. All people had been clinically evaluated and broadly phenotyped. Genotyping arrays and whole-genome sequencing KRN 633 inhibition had been performed on each member, and the resulting sequencing data had been analyzed utilizing a variety of obtainable bioinformatics equipment. We sought out uncommon variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in located within exon 1, and a novel de novo missense variant in test, which was negative for fragile X syndrome. A comparative genomic hybridization (CGH) microarray revealed a duplication on Xq13.1 inherited by the mother and shared by the unaffected sibling. There is no history of autism in close relatives; however, there are other distant cases of autism and pervasive developmental disorder in male individuals in the paternal side of the family (Supplemental Fig. 8). Concordance between Variant Detection Algorithms In this section, we explore detection reliability by measuring concordance among algorithm results across all sequenced individuals. Single-nucleotide variants, small insertions or deletions, and the detection of de novo variants of either class were compared across algorithms applied to raw whole-genome sequencing (WGS) data. Single-Nucleotide Variants (SNVs) and Small Insertions or Deletions (INDELs) GATK (the Genome Analysis Toolkit) and FreeBayes (FB) are algorithms that detect both SNVs and INDELs across the entire sequenced genome; as such, we report here the concordance between these two algorithms in detecting SNVs and INDELs. The observed mean concordance between GATK and FreeBayes was 79.3% and 56.6% for filtered SNV and INDEL calls, respectively. After filtering for Rabbit Polyclonal to NF1 high-quality variants according to each algorithm’s recommendation (see Methods), concordance between the algorithms increases by 5.7% and 5.4% for SNVs and INDELs, respectively. Table 2 summarizes the mean per person number of variants called by each algorithm. Table 2. Number KRN 633 inhibition of variants obtained by each algorithm before and after filtering Stop Gain Variant A KRN 633 inhibition de novo heterozygous nonsense mutation was found on the first exon of (Chr17: 4,442,191C4,458,926) in pedigree K21 (Fig. 3). This mutation is located at Chr17:4458481, is a G A substitution, and is annotated as being highly deleterious with a CADD score of 40, which corresponds to being within the top 0.01% of all possible SNVs in terms of its deleteriousness. The variant was not found in dbSNP Human Build 142 (Sherry et al. 2001), the Exome KRN 633 inhibition Variant Server (http://evs.gs.washington.edu/EVS/) or in any other person in the Simons Simplex Collection database. One proband from the SSC was found to have a de novo missense G T substitution KRN 633 inhibition in the same gene located at Chr17:4444853 causing an Arg Ser change. Only one person out of 71,164 unrelated individuals from the Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org) is reported to have this exact same mutation, indicating that this is a very rare variant. As the phenotype of this person in the ExAC database with the mutation is unknown, and also given that there are people with neuropsychiatric conditions in ExAC, no conclusions can be made from this alone. Sanger sequencing validated this mutation (Supplemental Fig. 1). Open in a separate window Figure 3. Genome Browser Display look at for the examine depths in the prevent gain (Chr17:4458481) mutation in the.