How to detect de novo mutations in exome data

Taking things apart. Looking for de novo variants using trio exome sequencing is a powerful technique to identify disease-related genes. After having introduced samtools during the last post, this will be post 2/3 in a series on how to perform an analysis of exome data for de novo variants. This time, I would like to take apart the methods that take us from Gigabyte BAM files to small tables with likely variants. So buckle up. Continue reading

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

Dysregulation of a microRNA in the 22q11.2 microdeletion

Genotype to phenotype. Recurrent microdeletions at various sites in the human genome are known risk factors for a broad range of neurodevelopmental disorders including epilepsy, autism, intellectual disability and schizophrenia. Despite the fact that the pathogenic role is well established, the mechanisms linking the microdeletion to the neurodevelopmental phenotype remain obscure. In contrast to monogenic disorders, various genes are included and functional studies are difficult. Now, a recent paper in Cell examines the role of a specific microRNA that is dysregulated in the 22q11.2 microdeletion. The results are surprising. Continue reading

Exploring samtools – Green Eggs and Ham (*.bam)

That Sam I Am.  The entire field of high-throughput genomics appears to be inspired by the American children’s book author Dr. Seuss. Given that we are currently reading through the original books almost on a daily basis due to the presence of a toddler in our home, mentioning *.sam files, *.bam files or sam2bam routines always makes me smile. However, this is not a post about children’s books; it’s about a likely 2013 trend in genomic research, the redefinition of the boundary between genome center and end user and the laptopification of life sciences. Continue reading

NRXN1 deletions and the double hit hypothesis of idiopathic epilepsy

Old friends. Structural genomic variants or Copy Number Variations (CNVs) play an important role in many neurodevelopmental disorders including epilepsy, autism, schizophrenia and intellectual disability. Many of the CNVs representing genetic risk factors overlap between these diseases. Now, a recent study in Epilepsia reports on the exon-disrupting deletions in NRXN1 as genetic risk factors for Idiopathic Generalised Epilepsy. NRNX1 deletions were previously reported in several other neurodevelopmental disorders. However, there is an interesting and unanticipated twist to the story. Continue reading

Hypermutability of autism genes: lessons from genome sequencing

Pushing past the exome. Family exome sequencing has become a standard technology to identify de novo mutations in neurodevelopmental disorders including autism, schizophrenia, intellectual disability and epilepsy. Despite the many advances in the field, exome data is confusing and difficult to interpret. Accordingly, we were wondering what the increase from exome sequencing to genome sequencing might add other than more data and more questions. Now, a recent paper in Cell reports on family-based whole-genome sequencing in autism. And some of the results are quite surprising. Continue reading

Eyelid myoclonia with absences meets GEFS+

Running in the family. Eyelid myoclonia with absences (EMA) is a rare generalized epilepsy syndrome characterized by brief episodes of myoclonic jerks that are often accompanied by an upward deviation of the eyeballs and an extension of the head. The EEG shows generalized spike-wave discharges during these episodes, and most patients are highly photosensitive. Therefore, it would be natural to think of EMA as related to other classical generalized epilepsies including Childhood Absence Epilepsy or Juvenile Myoclonic Epilepsy. Now, a recent paper in Epilepsia shows that the families of patients with EMA tell a slightly different story. Continue reading