Papers of the week – next-level mutation classifiers and 3’UTR variants in Dravet Syndrome

Bild1The future is now. This week’s publications of the week are about the next generation of in silico mutation interpretation, the power of a full genetic screen in neurodegenerative motor neuron diseases and a possible 3’UTR mutation in Dravet Syndrome.

Prioritization of noncoding variants with GWAVA. In the current issue of NATURE METHODS Ritchie and collegues present GWAVA, a framework, which prioritizes noncoding variants. The tool uses a wide range of annotations like Open chromatin, RNA polymerase binding from ENCODE data for variant classification. Then, they train the algorithm on a given disease (HGMD variants) against a control variant set from the 1k Genome Project. Therefore, GWAVA may present an alternative classifier to MutationTaster. However, both tools might be biased due to the low quality of the disease-associated regulatory variants annotated in HGMD.

Combined Annotation–Dependent Depletion (CADD).The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.” This is quite a strong statement from the Shendure group. Nevertheless, at first glance, this classifier published in this week’s issues of Nature Genetics might be the next generation of variant prediction tools.

Complete genetic analysis of hereditary spastic paraplegia. In a recent article in Science Novarino and contributors screen for mutations in patients with hereditary spastic paraplegia (HSP) and subsequently test the identified variants functionally. Moreover, additional candidate genes have been identified using network analysis of the identified disease-associated variants.

Supervisor. Recently Ingo and myself wrote about our latest career developments. We both mentioned the importance of scientific guidance by mentors. Here is an interesting article in Science Careers called “Getting the Mentoring You Need”. This might help graduate students and postdocs to define and pursue their career goals.

Rasmussen’s encephalitis (RE). In case you are interested in the latest advances regarding Rasmussen’s encephalitis. A current review by Varadkar et collaborators in The Lancet Neurology focuses on the clinical features of RE, the associated pathobiology and treatment advances.

3′ UTR SCN1A mutation in a patient with Dravet syndrome. Mutations affecting the coding sequence of the SCN1A gene cause a variety of epilepsy syndromes. However, the functional effects of 3’UTR variants are less clear. Zeng and collaborators present a 3’UTR variant identified in a patient with Dravet Syndrome, which decreases mRNA stability and might lead to reduced SCN1A protein expression.