Modifier genes in Dravet Syndrome: where to look and how to find them

Converging thoughts. During late 2013, I had several unrelated discussions about the possible role of genetic modifiers of SCN1A in Dravet Syndrome. To some extent, SCN1A is a paradox. One the one hand, the connection between Dravet Syndrome and SCN1A is one of the clearest connections between gene and disease that we see in genetic epilepsies. On the other hand, we see a remarkable phenotypic heterogeneity in families, and some presumably pathogenic SCN1A variants can also be identified in unaffected control individuals. This leaves us with the question whether there are genetic modifiers in Dravet Syndrome that might help provide some insight into additional mechanisms of disease. This post is a collection of 10 individual thoughts that emerged during the discussions last year. Continue reading

One in four – the carrier rate of recessive diseases

How frequent? With all the genetic information around, we are often wondering how much genetic morbidity is really hidden in our genomes. Yes, everybody is a knock-out for 1-3 genes, but in most cases, these variants do not cause disease. However, what happens if you apply genomics to estimate the burden of known disease variants? Now in a recent paper in Genetics in Medicine by Lazarin and colleagues, the carrier frequency for ~400 variants known to cause ~100 recessive disorders is investigated. 24% of all individuals are carriers for at least one recessive disorder. Continue reading

Exomes to the extreme to identify modifier gene in cystic fibrosis

Monogenic modifiers. Exome sequencing is a well established method to find causative genes in monogenic disorders, with probably more than 100 genes identified through this method in the last two years. In contrast to the ever-expanding list of monogenic diseases solved through massive parallel sequencing, there is widespread skepticism regarding its usefulness in complex genetic disorders. Now, a recent study in Nature Genetics suggests another application for exome sequencing, the identification of modifier genes in monogenic disorders. Continue reading