On the opposite end of the spectrum are typically common variants that have small or clinically negligible effects. Common diseases such as coronary artery disease and hypertension are caused, at the genetic level, by a combination of common and rare variants.17 Extracting Clinically Useful Information from WES Data Inherent to all medical tests are the technical limitations, and genetic AMN-107 testing by WES is no exception. The WES techniques are not

immune to false-positive and false-negative results. WES captures approximately 85% to 90% of the exons in the genome, which means WES does not adequately Inhibitors,research,lifescience,medical cover between 1,000 to 2,000 genes.18 Therefore, a “negative” result should not be considered an absolute finding. Clinical (phenotypic) information should be used to Inhibitors,research,lifescience,medical analyze the sequence output for an adequate coverage of the known and candidate genes, with

the understanding that this approach is inherently restricted and insufficient for discoveries of novel genes and mutations. It might also be necessary to capture the exons using an alternative method in scenarios wherein Inhibitors,research,lifescience,medical a strong genetic etiology is anticipated. False positive calls are often more problematic and vary dramatically according to the sequencing platform used and the depth of coverage, i.e., how many times each nucleotide is sequenced. Various sequencing platforms have different false positive rates and some are not suitable for medical sequencing, wherein accuracy is of utmost importance. For medical sequencing, typically an average coverage of 100x or greater would be desirable. This relatively high coverage increases the cost of Inhibitors,research,lifescience,medical sequencing yet significantly reduces the burden of deciphering true from false allele calls. The significance of this point must be underscored, as even a very low false positive allele call of 1% is sufficient to introduce a large number of false calls to the readout and complicate clinical applications of the findings. Increasing the mean coverage rate reduces the false

positive rate but does not totally eliminate them for various technical Inhibitors,research,lifescience,medical reasons. Accordingly, one has to merge the genetic data with the clinical information to discern the true causal variants from the false positive calls. The biggest challenge with the medical application of WES is identifying the true pathogenic variants out Anacetrapib of the 13,500 nsSNVs identified by WES. The following are various algorithms, including bioinformatics, used to restrict the number of putative pathogenic variants: A. Familial cosegregation. Perhaps the most valuable information is segregation of the variant with inheritance of the phenotype in families. Each meiosis, with some caveats, reduces the number of the candidate pathogenic variants by 50%. Thus, the best way to restrict the number of putative causal variants is to include as many family members as possible.