Whole Exome Sequencing Identifies Novel Homozygous LGI1 Variant Mimicking ADAM22-Related Pathologies in a Moroccan Family.

Abstract

Background: Epilepsy-related ligand-receptor complex, leucine-rich glioma-inactivated 1 (LGI1)-a disintegrin and metalloproteinase 22 (ADAM22), regulates neuronal excitability and synaptic transmission and has emerged as a determinant of brain excitability. Epilepsy-related variants have been described in both LGI1 and ADAM 22 genes. A partial epilepsy, autosomal dominant lateral temporal epilepsy (ADLTE) is caused by an LGI1 heterozygous variant. A recessive developmental and epileptic encephalopathy with infantile onset is due to homozygous inactivating ADAM22 variants.

Objective: We present the case of Moroccan siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene previously unreported in the homozygous state.

Methods: We performed whole-exome sequencing and family segregation analysis to identify and confirm the genetic cause of the condition in the affected siblings.

Results: The clinical features mimic ADAM22-related developmental and epileptic encephalopathy rather than the typical LGI1-associated autosomal dominant lateral temporal epilepsy. Family segregation analysis demonstrated variable expressivity, with asymptomatic carrier parents and a cousin with focal temporal epilepsy carrying the variant in the heterozygous state.

Conclusion: This case highlights a homozygous LGI1 variant previously unreported in the homozygous state, leading to a clinical presentation more reminiscent of ADAM22-related pathology rather than the classical ADLTE, expanding our understanding of LGI1-associated conditions.