Time flies – already thursday night again. Here are updates on study designs to identify rare pathogenic mutations in neurodevelopment diseases, an epilepsy animal model study as well as novel statistical frameworks for large genetic screens.
The placebo effect. In a recent paper in Science Translational Medicine the group of Kam-Hansen investigated the effect of altered placebo and drug labeling changes and its outcome in patients with episodic migraine. Their results suggest that the placebo accounted for more than 50% of the drug effect.
Sequencing of cousin pairs in complex disease studies. Cukier and collaborators present a family based screen for rare variants. They sequenced a pair of autism cousins and looked for rare variants identical by descent (IBD) for both. The investigation of 100 families demonstrated enrichment for variants in ASD candidate genes compared to random selected genes. Furthermore, they identified potential pathogenic variants in genes previous implicated in other neurodevelopmental diseases including epilepsy. This study design might be promising for mulitifactorial epilepsy syndromes like IGE.
Genotype-phenotype correlations. The amount of disease associated mutations is increasing rapidly. Statistical analysis will become feasible for the most prominent disease associated genes. Sasaki and colleagues demonstrate a correlation between mutations in the ATP1A3 gene and the variable phenotype of hemiplegia of childhood (AHC) in the latest edition of Neurology.
Dravet syndrome mice strains. Dravet syndrome may display variable clinical severity. In line with this observation, studies on SCN1A in mice have shown different results in the past. In a paper in Neurobiology of Disease, Mistry et al. have analyzed two different heterozygous Scn1a knockout mouse strains of Dravet syndrome. Each strain shows differences in hippocampal neurons that are strain- and age-dependent and correlate with epilepsy severity in mice. What is the genetic configuration for the difference in strains and are can the results be translated to Dravet syndrome?
A big week in schizophrenia genetics. This week two exome sequencing studies published in Nature report convergent results. The study by Purcell and colleagues investigated rare mutations in 2536 index patients, whereas the paper from Fromer et al. analyzed 623 trios for de novo mutations. Both studies highlight rare variant enrichment of gene sets affecting the activity-regulated cytoskeleton-associated scaffold protein (ARC). Moreover, resembling autism studies, both studies demonstrate that targets of the fragile X mental retardation protein (FMRP, product of FMR1) were enriched for mutations in patients. Should we expect similar results in epilepsy?
Genomic autopsy. In a recent paper in Epilepsia, Klassen et al. investigate the genetic landscape of a 3-year-old SUDEP proband with severe myclonic epilepsy of childhood. The authors identify several potential risk factors, but the results are complex and not easy to interpret. Do these genetic finding allow for risk assessment?
Framework for meta-analysis of rare Variants. Meta analyses have become a routine follow up after the initial GWAS. Large data sets will be essential to generate enough power especially for the detection of rare variants. In a new article in American Journal of Human Genetics, Lee and coworkers propose a new robust statistical framework for meta-analysis of rare variants.