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pLI score

Many of you perform trio exome sequencing to detect de novo mutations in an affected individual. This is for a good reason, as we all know that the probability of a coding DNM to be disease-causing is very high. However, sometimes there are more than a single loss-of-function DNM in an exome, or the gene in which it occurs is simple not related to any disease yet. We looked over the shoulder of experts that are facing such a case. They usually go through the ExAc cohort data and count how many LoF variants they can find in such a gene. Now, there is even a much more elegant way to do so. The ExAc consortium computed a score, called pLI, that indicates the probability that a gene is intolarent to a loss of function mutation. The statistical framework behind this score is explained in detail by Samocha, et al. Basically, the depature for a certain mutational class from the expectation is quantified. The figure below shows the distribution of z-scores for synonymous (gray), missense (orange), and protein-truncating, PTV (red) mutations in about 18,000 genes. There is a considerable right-shift in the distribution of missense and PTVs, indicating that more genes are intolarent to these classes of mutations.  The proportion of genes that are very likely intolerant of loss-of-function variation (pLI ≥ 0.9) is highest for ClinGen haploinsufficient genes, and stratifies by the severity and age of onset of the  haploinsufficient phenotype. Vice versa, if you encounter a missense or protein-truncating DNM in a gene with a pLI close to 1, the chances are high that this mutation is disease causing. As we don’t want you to count all the LoF mutations in a gene in ExAC by hand anymore, we added the pLI to the gene info in GeneTalk. See an example for ZEB2 below.