Age-dependent epileptic encephalopathy associated with an unusual co-occurrence of ZEB2 and SCN1A variants.

ABSTRACT

Mowat-Wilson syndrome is a genetic disorder associated with a variable phenotype including peculiar facial features associated with intellectual disability, epilepsy, language impairment, and multiple congenital anomalies caused by heterozygous mutation of the ZEB2 gene. The ZEB2 protein is a complex transcription factor that encompasses multiple functional domains that interact with the regulatory regions of target genes including those involved in brain development. Recently, it has been documented that ZEB2 regulates the differentiation of interneuron progenitors migrating from the medial ganglionic eminence to cortical layers by repression of the Nkx2-1 homeobox transcription factor. It has therefore been suggested that the deficit in ZEB2 may induce an imbalance of neuronal inhibition/excitation leading to epileptic seizures. Given the phenotypic variability of Mowat-Wilson syndrome, to date, a distinctive genotype-phenotype correlation has not been delineated. Here, we report a patient with a severe phenotype of Mowat-Wilson syndrome, associated with a novel heterozygous de novo frame-shift variant in the ZEB2 gene, as well as an additional novel heterozygous missense variant in the SCN1A gene, the mutation of which is known to affect NaV1.1-mediated sodium current in GABAergic interneurons. We hypothesize that the severe neurological phenotype of our patient may be influenced by the coexistence of both genetic mutations. [Published with video sequence].