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Open Access Editorial

A new era in the discovery of de novo mutations underlying human genetic disease

Chee-Seng Ku1*, Vasilis Vasiliou2 and David N Cooper3*

Author Affiliations

1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels väg 12B, Stockholm, SE-171 77, Sweden

2 Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd, Aurora, CO, 80045, USA

3 Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, Cardiff, CF14 4XN, UK

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Human Genomics 2012, 6:27  doi:10.1186/1479-7364-6-27

Published: 12 December 2012

First paragraph (this article has no abstract)

Germline mutations arise anew during meiosis in every generation. Such spontaneously occurring genetic alterations are termed de novo mutations and serve to describe those heritable mutations that neither parent possessed or transmitted. Thus, de novo mutations denote mutations that arose in the gametes of the parents as distinct from post-zygotic somatic mutations that arise during embryonic development. Studies of de novo mutations in the human genome have been very challenging owing to past technological limitations. However, the advent of high-through put next-generation sequencing (NGS) technologies has ushered in a new era in the study of de novo mutations. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can now be performed on parent-offspring trios to identify de novo point mutations in the entire genome or within protein-coding regions, respectively [1-3]. Although genome-wide de novo copy number variants (CNVs) were previously studied using microarrays [4-7], the study of de novo point mutations or single nucleotide variants (SNVs) required the advent of large-scale sequencing, which was not feasible using Sanger sequencing [1-3]. As with inherited mutations, de novo mutations range in size from point mutations and small indels of multiple bases to much larger CNVs and structural rearrangements [8]. In this article, we focus on de novo point mutations/SNVs and their implications for our understanding of the etiology of common complex diseases as well as rare Mendelian diseases.

Keywords:
de novo mutation; Exome sequencing; Human disease