Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

Stefan H. Lelieveld, Laurens Wiel, Hanka Venselaar, Rolph Pfundt, Gerrit Vriend, Joris A. Veltman, Han G. Brunner, Lisenka E. L. M. Vissers, Christian Gilissen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

49 Citations (Web of Science)

Abstract

Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.

Original languageEnglish
Pages (from-to)478-484
Number of pages7
JournalAmerican Journal of Human Genetics
Volume101
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

Keywords

  • SEVERE INTELLECTUAL DISABILITY
  • CHROMATIN REMODELING COMPLEX
  • EPILEPTIC ENCEPHALOPATHIES
  • FAMILIES
  • SUBUNITS
  • AUTISM
  • ANNOTATION
  • STABILITY
  • DOMINANT
  • SPECTRUM

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