Development of a Diagnostic Service for Comprehensive Assessment of De Novo Variants


De novo variants (DNVs) are a major cause of genetic disease in individuals with no family history of a given condition; recent evidence suggests that for severe developmental disorders the prevalence of disease caused by such variants may be as high as 1 in 213 live births (*1). Parents of children with DNVs have a risk of recurrence primarily owing to germline mosaicism. Next Generation Sequencing (NGS) has recently been shown to be a powerful method to detect low-level somatic mosaicism in the parents of children with DNVs (*2). These techniques have revealed that approximately 4% of apparently DNVs are in fact detectable in parental blood as low level mosaicism. These findings imply that such variants will be present in the germline, conferring a non-negligible recurrence risk for future offspring. I propose to establish a comprehensive service for the characterisation of DNVs: by determining the parental origin of such variants and identifying parents with low levels of mosaicism for a given pathogenic variant conferring an increased risk to future pregnancies.

(*) References 1. McRae et al., 2017. Prevalence and architecture of de novo mutations in developmental disorders. Nature, AOP doi:10.1038/nature21062 2. Rahbari et al., 2015. Timing, rates and spectra of human germline mutation, Nat Genet, 48(2), pp.126-132