Exome Sequencing Identifies Dual Mutations in Calcium Signaling Genes GNAO1 and ATP2B3 in a Patient with Early Infantile Epileptic Encephalopathy (EIEE) (P5.146)

OBJECTIVE: To present a case of early infantile epileptic encephalopathy (EIEE) associated with mutations in ATP2B3 and GNAO1. BACKGROUND: EIEE is an age-dependent epileptic encephalopathy with multiple seizure types especially tonic spasms, brain malformations and a suppression burst pattern on electroencephalogram. Mutations in several genes including GNAO1 have been reported in EIEE. DESIGN/METHODS: We report a 5-year-old boy with a history of EIEE, severe developmental and growth retardation, hypotonia and cerebellar ataxia since birth. He is severely delayed with very limited interactions with environment. Infantile spasms were treated successfully with ACTH after trial of Pyridoxine, Phenobarbital, Levetiracetam, Topiramate, and Vigabatrin but he continues to have focal seizures. He currently receives Levetiracetam, Zonisamide and Clobazam and has no generalized tonic clonic seizures after Clobazam was started. Routine metabolic testing, mitochondrial DNA sequencing, SCN1A, STXBP1, POLG gene sequencing and chromosome microarray did not reveal any abnormalities. Whole exome sequencing was performed using DNA from patient and both parents. RESULTS: Exome sequencing revealed a maternally-inherited missense alteration in ATP2B3 (c.3338C>T/p.T1113M) as well as a de novo missense alteration in GNAO1 (c.133G>C/p.G45R). Both genes are associated with calcium signaling in epinephrine pathway. Mutations in ATP2B3 gene have been reported in X-linked spinocerebellar ataxia-1. GNAO1 gene mutations have so far been reported in 7 patients with EIEE. Both genes were either co-expressed, co-localized or otherwise interacted with multiple other genes mutated in EIEE. CONCLUSIONS: (1) Both mutations were in genes that are involved in calcium signaling and form network with other genes mutated in EIEE. (2) Identification of dual mutations has genetic counseling implications as mutation in GNAO1 gene is de novo with low recurrence risk while ATP2B3 mutation is an X-linked inherited mutation with 50[percnt] recurrence risk in a subsequent male offspring. Disclosure: Dr. Ueda has nothing to disclose. Dr. Serajee has nothing to disclose. Dr. Huq has nothing to disclose.