Fig. 3: Compound heterozygous variants.

a Illustration of the unnormalized squared mutational target computed for each observed comphet variant in a gene across the cohort (RaMeDiES-CH, Supplementary Fig. 11) or in an individual across the genome (RaMeDiES-IND, Supplementary Fig. 12). “Like” variants refer to those of the same variant class (i.e., coding SNVs [CS], coding indels [CI], intronic SNVs [IS], intronic indels [II]) and within the same functionality score and minor allele frequency thresholds. b Top ranked genes resulting in the best enrichment statistic computed for RaMeDiES-IND. Putative candidates refer to genes that remain candidates for pathogenicity due to their phenotypically-relevant tissue expression, but where there is not enough functional evidence or published gene–disease relationships to establish causality at this time. c Overlap between phenotypes associated with MED11 and those exhibited by the affected patient. d RNA-Seq reads from whole blood samples aligned to first two exons and first intron of MED11 for proband (black), dad (blue), mom (purple) and two tissue-matched control samples (gray). Thin green line represents the intron, solid boxes represent protein-coding exonic regions, and the dotted box represents the 5’ untranslated region of MED11. (e) Proband exhibits significant retention of the first intron relative to parents and fifty-three tissue-matched control samples. Intron retention ratio is calculated as the (median read depth of first intron) / (number of reads spanning first and second exons + median read depth of first intron).