Epilespy, Autosomal Dominant Lateral Temporal, via the LGI1 Gene

Autosomal Dominant Lateral Temporal Epilepsy (ADLTE), also named Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF), is an idiopathic focal epilepsy syndrome characterized by focal seizures initiated in the temporal lobe with prominent auditory features or aphasia. The most common auditory features are simple unformed sounds such as humming, buzzing, or ringing; less common forms are distortions or complex sounds. Most patients have secondarily generalized seizures, usually accompanied by simple partial and complex partial seizures. MRI is normal and Interictal EEG is often normal too. However, focal epileptiform abnormalities (usually localized to the temporal region) can be found in up to two thirds of patients. Age of onset varies from adolescence to the second decade of life. Seizures are well controlled by antiepileptic treatment, but recur after drug discontinuation. The prognosis is favorable in most cases (Michelucci et al. 2003; Ottman et al. 2004; Di Bonaventura et al. 2011).

Autosomal Dominant Lateral Temporal Epilepsy is inherited in an autosomal dominant manner. Pathogenic variants in LGI1 cause this type of epilepsy (Wilmshurst et al. 2015). The majority of pathogenic variants reported in LGI1 gene are missense. Others include nonsense, splicing, small deletions/duplications, as well as large deletions compassing the LGI1 locus (Michelucci et al. 2003; Lee et al. 2014; Fanciulli et al. 2012). Uncommonly, low penetrance can be observed due to the effect on protein secretion by certain pathogenic LGI1 variants (Di Bonaventura et al. 2011). Pathogenic variants in the LGI1 gene can occur in both familial and sporadic cases. De novo pathogenic variants have been reported, but the proportion is very low, around 2% in affected families (Nobile et al. 2009).

The leucine-rich glioma-inactivated 1 (LGI1) gene encodes a secreted protein. This protein is linked to human seizures of both genetic and autoimmune aetiology. A transgenic mouse model revealed that the LGI1 protein is required from embryogenesis to adulthood to maintain proper circuit functioning (Boillot et al. 2014). However, it remains unclear whether secreted and/or cytoplasmic LGI1 protein is involved in the circuit hyperexcitability that triggers seizures.

Pathogenic variants in the LGI1 gene have been reported in up to 50% of families with Autosomal Dominant Lateral Temporal Epilepsy (Berghuis et al. 2013).

This test provides full coverage of all coding exons of the LGI1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.