Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.

Purpose Identifying structural variations (SVs) associated with developmental disorder (DD) patient phenotype missed by conventional approaches. Methods We have developed a novel SV discovery approach that mines split-read information, 'InDelible', and applied it to exome sequencing (ES) of 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study. Results Using InDelible we were able to find 59 previously undetected variants in genes previously associated with DD, of which 49.2% (29) had phenotypic features that accord with those of the patient in which they were found, and were deemed plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.0% (n = 29 variants). Of particular interest were seven confirmed de novo SVs in the gene MECP2; these variants represent 31.8% of all de novo protein truncating variants in MECP2 among DDD patients. Conclusion InDelible provides a rapid framework for the discovery of likely pathogenic SVs that are likely to be missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES.