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GeneTalk’s frequency filter now based on more than 65,000 exomes

Standing on the shoulders of giants

Power does not consist in striking with force but in striking with frequency! We adapted slightly Balzac’s catechism so that it can now be applied to sequence variants. We updated GeneTalk’s frequency filter with the genotype data of more than 65,000 exomes from the Exome Aggregation Consortium. Thanks Daniel MacArthur and all the others involved for this great data set!

Many of us are analyzing rare diseases. So rare, that often less than one individual out of ten thousand people is affected. For a patient of consanguineous parents that is suffering from a recessive illness a common filtering approach was to apply a frequency filter for homozygous genotypes of 0.001. The rationale behind this parameter settings is the following: In a highly penetrant disorder cannot be caused by an allele that occurs in a homozygous state more frequently than the incidence of the disease.  Well, if this holds true, why are we not using a filtering cutoff of 0.0001? It basically didn’t make a difference so far, because the sample size of the control group was about a few thousand individuals from the 1000 genomes project. There was simply very little power in detecting homozygous genotypes with a frequency of 0.0001. However this now chances with the 65,000 exomes from the ExAC. The probability that we will find at least one healthy individual that is homozygous for an allele of frequency 0.01 that is not deleterious is above 50%. (Thus is the calculus: Assuming Hardy Weinberg Equilibrium for the allele, the probability that none of 65,000 individuals is homozygous is (1-(0.01)^2)^65,000).

That means you will tremendously benefit in your analysis from the new frequency filter in GeneTalk. So strike it with frequency!