Figure 3.

Two extreme examples of single and multigenic biological complexity in epileptic brain. Left, epileptic phenotype in mouse mutant with a solitary Nova2 knockout arises from alterations in splice patterns of a cassette of 34 synaptic proteins⁷⁸ (reproduced with permission from ref. 78). Many of these targets are known monogenic causes of epilepsy. Right, extensive multigenic complexity in the ion channel variant profile (channotype) of individuals with sporadic epilepsy is similar to that found in unaffected cases. Many affected individuals show multiple non-synonymous single nucleotide variants in human epilepsy genes (hEP), and clinical status depends on the pattern, not absolute load, of variants. In silico modeling of combinatorial effects of multiple ion channel variants in a single model neuron demonstrates how profiles produce a spectrum of single cell firing patterns⁸¹ (reproduced from ref. 81 with permission from Elsevier).