J Med Genet 50:203-211 doi:10.1136/jmedgenet-2013-101519
  • Review

From the periphery to centre stage: de novo single nucleotide variants play a key role in human genetic disease

Editor's Choice
  1. David N Cooper4
  1. 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Neurology, National Neuroscience Institute, Singapore, Singapore
  3. 3Duke-National University of Singapore Graduate Medical School, Singapore General Hospital, Singapore, Singapore
  4. 4School of Medicine, Institute of Medical Genetics, Cardiff University, Cardiff, UK
  1. Correspondence to Dr Chee-Seng Ku, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden; cheeseng.ku{at} and Professor David N Cooper, Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; cooperDN{at}
  • Received 4 January 2013
  • Accepted 9 January 2013
  • Published Online First 9 February 2013


Human germline mutations arise anew during meiosis in every generation. Such spontaneously occurring genetic variants are termed de novo mutations. Although the introduction of microarray based approaches led to the discovery of numerous de novo copy number variants underlying a range of human genetic conditions, de novo single nucleotide variants (SNVs) remained refractory to analysis at the whole genome level until the advent of next generation sequencing technologies such as whole genome sequencing and whole exome sequencing. These approaches have recently allowed the estimation of the mutation rate of de novo SNVs and greatly increased our understanding of their contribution to human genetic disease. Indeed, de novo SNVs have been found to underlie various common human neurodevelopmental conditions such as schizophrenia, autism and intellectual disability, as well as sporadic cases of rare Mendelian disorders. In many cases, however, confirmation of the pathogenicity of identified de novo SNVs remains a major challenge.