Clustering de novo missense mutations in intellectual disability

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A study entitled “Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes” led by Christian Gilissen was published in the American journal of human genetics on 1 September.

The publication is part of the PhD projects of Stefan Lelieveld (Human Genetics) and Laurens van de Wiel (CMBI & Human Genetics) and identifies three novel candidate neurodevelopmental-associated genes based on clusters of de novo missense mutation in patients.

Haploinsufficiency (e.g. mRNA truncating mutations, where the gene product of one of the two gene copies is lost) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency mechanisms, such as gain-of-function (the altered gene product possesses a new or abnormal molecular function) and dominant-negative (the altered gene product has lost its function) mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only specific (functional) regions or base pairs of a gene. The authors exploited this property and developed a method to specifically identify genes with spatial clustering patterns of de novo mutations. “We applied our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders.” The analyses resulted into the identification of 15 genes with clustering mutations, including three novel candidate neurodevelopmental-associated genes. To show that the mutations in these genes are disrupting protein-function instead of degradation due to misfolding, the authors modeled the missense mutations in 3D protein structures. “3D modeling of these mutations on their protein structures showed 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 haploinsufficiency.”

These findings of the authors indicate a larger contribution of non-haploinsufficient mechanisms to neurodevelopmental disorders than previously thought.


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