Expanding the electroclinical spectrum of TANC2-related disorders: Lennox–Gastaut syndrome and related developmental epileptic phenotypes

Abstract

Objective

Neurodevelopmental disorders (NDDs) and epilepsy are often associated. Increasing evidence highlights a pivotal role for pathogenic variants in genes encoding synaptic scaffolding proteins. Within this group, TANC2 has recently been implicated in intellectual developmental disorder with autistic features and language delay, with or without seizures; however, its full clinical spectrum and contribution to specific epileptic encephalopathies remain incompletely defined.

Methods

We describe the electroclinical and developmental features of three patients carrying truncating TANC2 variants identified through trio-exome sequencing within the European collaborative platform NETRE. Clinical, neuropsychological, and EEG data were collected and compared with prior reports.

Results

Case #1 met Lennox–Gastaut syndrome (LGS) criteria, showing early drug resistance followed by partial cognitive recovery and sustained seizure control on felbamate monotherapy. Case #2 presented with ASD and multiple seizure types—including focal, atypical absence, and tonic—finally reaching prolonged remission and borderline intellectual functioning. Case #3 showed early-onset, drug-resistant polymorphic seizures with persistent bifrontal epileptiform discharges and severe developmental impairment, consistent with an LGS-like phenotype, with seizure freedom achieved under a limited polytherapy regimen.

Significance

Our findings expand the electroclinical spectrum of TANC2-related disorders, supporting a continuum ranging from NDD-associated epilepsy to DEE, including LGS in selected patients.

Plain Language Summary

TANC2 is a gene involved in brain development and synaptic function. Changes in this gene have been linked to neurodevelopmental disorders, autism, intellectual disability, and epilepsy. We describe three individuals with previously unreported truncating TANC2 variants and different epilepsy phenotypes, including one patient fulfilling criteria for Lennox–Gastaut syndrome (LGS) and another with LGS-like features. Although seizures were initially difficult to treat in some cases, seizure control was eventually achieved. These findings expand the known clinical spectrum of TANC2-related disorders and suggest that selected patients may have a more favorable seizure course than expected.