De Novo Mutations in Human Inherited Disease


De novo mutations are so‐called because neither parent of the individual concerned is a constitutive carrier of the mutation since the lesion will have either originated in a germ cell from one of the parents or alternatively in the fertilised egg during early embryogenesis. The majority of such mutations arise in the paternal germline as a consequence of the greater opportunity for DNA replication errors to occur owing to the much higher number of cell divisions. With the production of large quantities of next‐generation sequencing data from hundreds of genes involved in neurodevelopmental disorders such as schizophrenia, autism spectrum disorder, intellectual disability and epilepsy, de novo mutations have become a major focus of attention. As the number of reported de novo mutations increases, the challenge becomes how to distinguish those mutations that have a truly detrimental effect on the protein product from those that are low‐risk or even neutral alleles.

Key Concepts

  • De novo mutations arise either in the parental germ cells or in the fertilised egg during embryogenesis.
  • De novo mutations arise more commonly in the paternal germline owing to the higher number of cell divisions.
  • Clusters of de novo mutations are found on some chromosomes and these are mainly of maternal origin.
  • De novo mutations are frequently found in the genomes of individuals affected by neurodevelopmental conditions such as autism spectrum disorder, schizophrenia, epilepsy, bipolar disorder and intellectual disability.
  • Ascertaining the genotype–phenotype relationship is challenging because some of the de novo mutations detected in patients may be neutral alleles.

Keywords: de novo mutation; non‐Mendelian inheritance; Mendelian disease; neurodevelopmental disorders; mosaicism; mutation clustering

Figure 1. Numbers of male and female chromosomal replications in the germline. Source: Data from Crow .


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Further Reading

Huang AY, Yang X, Wang S, et al. (2018) Distinctive types of postzygotic single‐nucleotide mosaicisms in healthy individuals revealed by genome‐wide profiling of multiple organs. PLoS Genet. 14: e1007395.

Kieffer E, Nicod J‐C, Gardes N, et al. (2018) PGD for de novo mutation: when mosaicism prevents PGD setup and leads to genetic counselling revision. Reproductive BioMedicine Online 36: e37.

Marco EJ, Aitken AB, Nair VP, et al. (2018) Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction. BMC Medical Genomics 11: 50.

Qin L, Wang J, Tian X, et al. (2016) Detection and quantification of mosaic mutations in disease genes by next‐generation sequencing. Journal of Molecular Diagnostics 18: 446–453.

Wilfert AB, Sulovari A, Turner TN, et al. (2017) Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications. Genome Medicine 9: 101.

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Oliveira, Sofia, Cooper, David N, and Azevedo, Luisa(Sep 2018) De Novo Mutations in Human Inherited Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027866]