Epileptic encephalopathy

Gene: TSC1

A missense variant was originally reported in PMID: 12112044 but this has been reclassified in OMIM as a variant of unknown significance due to the gene-disease association having been refuted by PMID:19175396 which reported sequence alterations in the TSC1 and TSC2 genes in lesional brain tissue and blood of Focal cortical dysplasia patients are found in a similar frequency to that of a normal population. A more recent publication (PMID: 28215400) provides more evidence for somatic brian mutations in TSC1 and TSC2 to be implicated in FCD2. They took 40 patients who were negative for MTOR mutations, and found candidate causative somatic brian variants in TSC1 or TSC2 in 5 patients (3 different missense variants). In vitro assays provided evidence to show that the mutations induced activation of mTOR kinase by disturbing the formation or function of the TSC1-TSC2 complex. Using in utero CRISPR-Cas9 somatic genome-editing system, a focal cortical disruption of the TSC1-TSC2 complex, encoded by Tsc1 and Tsc2 was reported to cause spontaneous behavioral seizures as well as migration defects and cytomegalic neurons, consistent with the neuropathological phenotype of individuals with FCD2. Two of the 3 variants reported were found at a low frequency in ExAC Browser (1.65x10-5 and 3.34x10-5).

Created: 22 Sep 2017, 2:54 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Focal cortical dysplasia, type II, somatic 607341

Publications

• 28215400
• 19175396
• 16114042
• 12112044