The phenotypic spectrum of YWHAG-related epilepsy: From mild febrile seizures to severe developmental delay and epileptic encephalopathy.

Aim: To explore the phenotypic spectrum and refine the genotype-phenotype correlation of YWHAG-related epilepsy.

Method: This study used a retrospective cohort design to evaluate the clinical data of 15 patients with epilepsy and YWHAG variants in our Chinese cohort (nine males, six females; median age: 6 years 4 months; range: 1 year 6 months-12 years 8 months) and 40 patients with epilepsy with YWHAG variants from published studies (21 males, 19 females; median age: 10 years; range: 3 years-67 years).

Results: In our cohort, seven variants were de novo and five were new. Seizure onset for 14 of 15 patients occurred within the first 2 years of life. Nine of 15 patients had a history of febrile seizures. Seizure types included generalized tonic-clonic seizures (GTCS) and myoclonic seizures. Developmental delay was present in 11 of 15 patients. Three patients were diagnosed with febrile seizures plus, one was diagnosed with myoclonic epilepsy in infancy, one had infantile epileptic spasm syndrome, and 10 had developmental and epileptic encephalopathy that could not be further classified into a specific epilepsy syndrome. Seizures were controlled in 7 of 15 patients; most were treated with valproate and levetiracetam. Collectively, in our cohort and from published studies, most variants (38 of 55, 69.1%) were located in the highly conserved triad (HCT) domain of Arg132-Arg57-Tyr133. Mild phenotypes were more frequently observed in patients with variants located outside the HCT domain, with a significant difference of 70.6% versus 27.0% (p < 0.01).

Interpretation: Most patients with YWHAG variants were diagnosed during infancy. The most common seizure types were GTCS and myoclonic seizures. The phenotypic spectrum of epilepsy ranged from mild febrile seizures to severe developmental delay and epileptic encephalopathy. Most variants were localized in the HCT domain; variants residing outside the HCT domain were correlated with milder phenotypes.