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A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease

Molecular Psychiatry volume 18, pages 141–153 (2013)Cite this article

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Abstract

The study of de novo point mutations (new germline mutations arising from the gametes of the parents) remained largely static until the arrival of next-generation sequencing technologies, which made both whole-exome sequencing (WES) and whole-genome sequencing (WGS) feasible in practical terms. Single nucleotide polymorphism genotyping arrays have been used to identify de novo copy-number variants in a number of common neurodevelopmental conditions such as schizophrenia and autism. By contrast, as point mutations and microlesions occurring de novo are refractory to analysis by these microarray-based methods, little was known about either their frequency or impact upon neurodevelopmental disease, until the advent of WES. De novo point mutations have recently been implicated in schizophrenia, autism and mental retardation through the WES of case-parent trios. Taken together, these findings strengthen the hypothesis that the occurrence of de novo mutations could account for the high prevalence of such diseases that are associated with a marked reduction in fecundity. De novo point mutations are also known to be responsible for many sporadic cases of rare dominant Mendelian disorders such as Kabuki syndrome, Schinzel–Giedion syndrome and Bohring–Opitz syndrome. These disorders share a common feature in that they are all characterized by intellectual disability. In summary, recent WES studies of neurodevelopmental and neuropsychiatric disease have provided new insights into the role of de novo mutations in these disorders. Our knowledge of de novo mutations is likely to be further accelerated by WGS. However, the collection of case-parent trios will be a prerequisite for such studies. This review aims to discuss recent developments in the study of de novo mutations made possible by technological advances in DNA sequencing.

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Acknowledgements

We would like to thank Touati Benoukraf and Mengchu Wu (Cancer Science Institute of Singapore) for discussion.

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Authors and Affiliations

  1. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore

    C S Ku & N Naidoo

  2. Department of Pediatrics/Human Genetics, McGill University Health Center, Montreal, QC, Canada

    C Polychronakos

  3. Department of Neurology, National Neuroscience Institute, Singapore, Singapore

    E K Tan

  4. Duke-National University of Singapore Graduate Medical School, Singapore General Hospital, Singapore, Singapore

    E K Tan

  5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Y Pawitan

  6. Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece

    D H Roukos

  7. Biosystems and Synthetic Genomic Network Medicine Center, Ioannina University, Ioannina, Greece

    D H Roukos

  8. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK

    M Mort & D N Cooper

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  1. C S Ku
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  2. C Polychronakos
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  3. E K Tan
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  4. N Naidoo
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  5. Y Pawitan
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  6. D H Roukos
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  7. M Mort
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  8. D N Cooper
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Correspondence to C S Ku or D N Cooper.

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Ku, C., Polychronakos, C., Tan, E. et al. A new paradigm emerges from the study of de novo mutations in the context of neurodevelopmental disease. Mol Psychiatry 18, 141–153 (2013). https://doi.org/10.1038/mp.2012.58

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  • DOI: https://doi.org/10.1038/mp.2012.58

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