Genome meets phenome to find novel recessive diseases

N=1. Even though many recessive disorders have been identified through next-generation sequencing, there is a major conceptual problem when it comes to interpreting the results of these studies. Recessive disorders are very rare and it is sometimes difficult to assess whether a given variant is truly disease-causing or simply an innocent bystander. A recent study in Nature Genetics has developed a novel concept to identify recessive disorders that rise above the overall genomic noise, finding four novel recessive disorders. In addition, the authors have enhanced their analysis by a statistical analysis of disease phenotypes.

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How to find recessive disease genes for epileptic encephalopathies

The E2 story continues. There has been major progress in identifying the role of de novo mutations in infantile spasms and other epileptic encephalopathies. Over the last two years, more than 20 new genes for epileptic encephalopathies were discovered and we have good evidence suggesting that de novo mutations play a major role in these disorders. Moreover, we have gotten a good sense on how complicated it can be to call a de novo mutation pathogenic given the flood of rare genetic variants in the human genome. However, de novo mutations are not what we think about clinically when assessing a patient with new-onset epileptic encephalopathy. In a clinical setting, we are often concerned about underlying metabolic disorders, many of which are recessive. Accordingly, we felt that the next task of the E2 consortium was to assess the role of inherited variants in epileptic encephalopathies. Just to tell you in advance, it is not as easy as it sounds.

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