Landscape of parental postzygotic mutations in >11,000 rare disease trios

Postzygotic mutations (PZMs) arising post-fertilisation, prior to primordial germ cell specification, may be subsequently inherited by both somatic and germ cells, causing somatic mosaicism in the parent as well as being passed to offspring. These early embryonic mutations often go undetected in clinical sequencing due to their low variant allele fraction (VAF) and are typically excluded by standard variant filtering pipelines. To overcome this limitation, we developed a bioinformatic approach to detect PZMs using standard-depth (∼30X) whole genome sequencing data from 12,015 parent-offspring trios in the Genomics England 100,000 Genomes Project. We identified 1,015 high-confidence autosomal early PZMs. These mutations showed no parental sex-bias and exhibited a monomodal VAF distribution centred around 5% in blood. PZMs displayed a mutational spectrum distinct from de novo mutations, although both appeared to be driven by mutational signatures SBS1 and SBS5. Notably, we identified a subset of PZMs likely contributing to the clinical phenotype in affected children. This work demonstrates that postzygotic mosaicism represents a rare but clinically relevant source of diagnostic variation in rare disease and can be detected from standard sequencing data. Incorporating PZM detection into clinical workflow could improve diagnostic yield and provide more accurate recurrence risk estimates for affected families.