Objective To investigate the clinical and genetic characteristics of acute necrotizing encephalopathy (ANE) with trilaminar appearance (TA) of insular. Methods The clinical data of patients from one family diagnosed with ANE were collected and analyzed. Results The proband was a boy; he started development of convulsion and disturbance of consciousness at the age of 4 . 5 years, and a history of febrile convulsion at the age of 1 year. Head MRI showed symmetrical multifocal lesions with TA in the insular lobe. There were 6 patients in the family with onset ages ranging from 6 months to 50 years. The main symptoms of the patients were convulsion after fever or status convulsions and disturbance of consciousness, and 3 patients died of status convulsions. Whole-exon sequencing analysis confirmed that the pathogenic gene was RANBP2 (NM_ 006267 ; c. 1754 C>T [p.T 585 M]). Immunotherapy and energy support could improve the prognosis. Conclusion This study reported for the first time that TA can appear in the insula.