Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies

Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries ∼22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases. Author Summary: Sequencing the coding regions of the human genome is becoming a standard approach in identifying causal genes for human Mendelian diseases. Researchers often rely on multiple functional prediction methods/tools to separate the candidate causal mutation(s) from other rare mutations in these studies. In this paper, we propose the use of a statistical model to combine prediction scores from multiple methods and to estimate the chance of a rare mutation being Mendelian disease-causing (or pathogenic). We found that our model using all or some individual prediction methods consistently outperforms other prediction methods examined and could exclude more than 55% of rare non-pathogenic mutations in an individual genome. Unfortunately, no method was able to discriminate between autosomal dominant and autosomal recessive disease mutations. In addition, based on the predictions of our model, we estimated that a person can carry ∼22 pathogenic derived alleles at least, which if present at the same position in the genome may lead to Mendelian diseases.