Combinations of rare variants contributing to intellectual disability (ID) phenotype. (A) An outline of the approach used to identify and validate mutated gene pairs and triplets enriched in probands with ID is shown. We tested whether mutated gene pairs identified as significant in one cohort (SPARK) are also associated with severe phenotypes in an independent cohort (SSC). To test this, we obtained the mean IQ score of individuals from the SSC cohort carrying significant combinations identified from the SPARK cohort. Empirical P-values were then calculated based on the deviation of the mean IQ from the distribution of mean IQ scores obtained from 10,000 random draws in the simulation. (B) The mean IQ of individuals with mutated gene pairs in the SSC cohort was significantly lower (empirical P-value = 0) when compared to the distribution of mean IQ scores obtained from the simulation. (C) Histogram shows the distributions of IQ scores of SSC probands who carried mutations in either of the genes versus both constituent genes of the significant gene pairs. The distributions were significantly different from each other (P-value = 1.302 × 10−16, Kolmogorov–Smirnov test).
