This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders.
Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently).
Here, we reprogrammed human skin fibroblasts from a 13-year-old male patient with developmental and epileptic encephalopathy carrying a point mutation (c.982T>G, p.Leu328Val) in KCNA2 to human induced pluripotent stem cells (iPSCs) (HIHDNEi001-A).
Recently, four patients with epileptic encephalopathy (EIEE17) were found to have mutations in GNAO1, the most abundant G protein in brain, but the mechanism of this effect is not known.
By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy.
We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy.
We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation.
Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy.
Using whole exome sequencing we found a de novo heterozygous, missense mutation of FHF1 (p.Arg52His, NM_004113), a mutation that has been very recently described in 7 patients with an early onset epileptic encephalopathy.
While classically thought to act at sodium channels, lamotrigine also modulates the activity of the P/Q-type calcium channel, making it a candidate for precision therapy for patients with epileptic encephalopathy due to CACNA1A pathogenic variants.
To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2.