Rare human knockouts. Recessive disorders arise when both copies of a causative gene are affected by mutations. These diseases are thought to be a very rare occurrence, but the cumulative impact of these conditions is not known. Population genome sequencing offers the possibility to assess the spectrum and distribution of potentially causative mutations in large groups of individuals. In a recent publication from deCODE published in Nature Genetics, the authors examine the population spectrum of rare human knockouts using the unique genetic data and population structure of the Icelanders. Here is the story about potential candidate genes identified by population genetics. Continue reading
Tag Archives: compound heterozygous
The return of TBC1D24
First of its kind. In 2010, a virtually unknown gene became the first epilepsy gene to be discovered through massive parallel sequencing techniques. This gene, TBC1D24, was found in two recessive families with different types of epilepsy. Afterwards, it became silent around this gene with no further findings. Now, a recent paper reports on a third family with a mutation in this gene with a complex phenotype of epileptic encephalopathy and movement disorders. As the mutation is located in an alternative exon of this gene, this raises important issues on how we identify and interpret mutations. Continue reading
Recessive mutations in autism – the return of hidden metabolic disorders
My wrong guesses of 2012. Two weeks ago during a presentation, I had to admit that there is little evidence for a large contribution of recessive or compound heterozygous mutations in epileptic encephalopathies. At the beginning of 2012, I had initially suggested that recessive or compound heterozygous mutation of known neurometabolic disorders could be identified through exome sequencing in sporadic epileptic encephalopathies. However, as of 2013, there is little evidence for this in our data or the data from other consortia. Now, two papers in Cell suggest a significant contribution of recessive mutations in autism including a revival of the “hidden neurometabolic hypothesis”. Continue reading
