Developmental and epileptic encephalopathy in a boy with a novel pathogenic IQSEC2 variant

Abstract

  The IQSEC2 gene on chromosome Xp11.22 encodes a guanine nucleotide exchange factor (GEF), which is enriched at the postsynaptic density of excitatory synapses where it controls excitatory synaptic transmission. Since 2010, when IQSEC2 variants were discovered in families with X-linked intellectual disabilities, the spectrum of clinical features has expanded with early-onset seizures, as a frequent comorbidity in both affected male and female patients. Herein, we describe a boy with a pathogenic variant in exon 1 of IQSEC2, NM_001111125.2 : c.693del [p. (Thr232Profs^＊25)], leading to a loss of all functional domains on the longest IQSEC2 isoform. Our patient has shown hypotonia and strabismus since infancy, later presenting with severe intellectual disabilities, including autism. Brain MRI showed brain atrophy, a thin corpus callosum, and periventricular T2 hyperintensities. He developed myoclonic seizures since 2 years of age in addition to tonic-clonic seizures and atypical absence seizures. An interictal EEG showed generalized polyspikes and wave discharges ; the epilepsy was refractory to antiepileptic drugs, and he underwent corpus callosotomy at 4 years of age, which led to disappearance of the drop attacks and improvement of facial expression ; however, his psychomotor development remained to be severely impaired. Overall, his clinical course matches that of developmental and epileptic encephalopathy (DEE). These clinical manifestations such as DEE with the characteristic MRI findings are considered to be the most severe form of the IQSEC2-related disorders.