New insights into the generation and role of de novo mutations in health and disease

Abstract

Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent–offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

De novo and inherited pathogenic variants in collagen‐related osteogenesis imperfecta

“…The results from the analysis of mutational architecture also aligned with those of previous studies (Acuna‐Hidalgo et al., ; de Ligt et al., ; Stover & Verrelli, ). The majority of nucleotide changes in this study were G>A transitions, altering the chain domain of a protein.…”

“…As noted by Acuna‐Hidalgo et al. (), de novo variants do not differ in prevalence across populations and are the main source of neurodegenerative and developmental disorders. With the availability of sequencing techniques, our understanding of the role of de novo pathogenic variants in both common and rare genetic disorders is changing, bringing with it increased knowledge about newly arising pathogenic variants.…”

Parental age and childhood cancer risk: A Danish population-based registry study

“…An increased rate of de novo mutations has been more consistently linked with advanced paternal age than maternal age, likely due to the greater number of cell divisions in spermatogonial cells compared to oogonial cells. Despite more limited evidence on a link between de novo point mutations and older maternal age, older maternal age has been well-established as a risk factor for chromosomal nondisjunction involved in aneuploidies [39]. Down syndrome is one example of a chromosomal abnormality that is mostly of maternal origin and occurs more frequently with older age, with mothers 40+ at childbirth having a 17% higher risk of having a child with Down syndrome [40].…”

Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder

“…22 These findings have important implications for recurrence risk and clinical testing, which are still not widely appreciated. 14,22,46,72,73 While the recurrence risk for de novo mutations is generally thought to be low ($1%), finding the presence of a mutation, even at low levels, in a parent dramatically increases this risk to a previously estimated >5%. 46,72,73 The risk may be dramatically higher for specific mutations, depending on their embryonic timing and distribution within the germ cells.…”