Dravet Syndrome and rare variants in SCN9A

How monogenic is monogenic? Dravet Syndrome is a severe epileptic encephalopathy starting in the first year of life. More than 80% of patients have mutations or deletions in SCN1A, which makes Dravet Syndrome a relatively homogeneous genetic epilepsy. In addition to SCN1A, other genetic risk factors for Dravet Syndrome have been suggested, and current, large-scale studies including EuroEPINOMICS-RES are studying the genetic basis of the minority of Dravet patients negative for SCN1A. A recent paper in Epilepsia now suggests that a significant fraction of patients with Dravet Syndrome also carry rare variants in SCN9A in addition to the mutations in SCN1A. Is a mutation in SCN1A not sufficient to result in Dravet Syndrome, but needs additional genetic modifiers? 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