Background: Pathogenic variants in SCN2A, a gene encoding the voltage-gated sodium channel (Nav1.2), contribute to a spectrum of epilepsy and neurodevelopmental disorders. The recurrent 16p11.2 duplication is a copy number variant risk loci commonly associated with developmental delays affecting speech and motor functions, with increased seizure risk.

Case Description: Following a normal pregnancy, neonatal and early developmental period, this female patient was noted to have delayed developmental milestones and failure to thrive at 8 months of age. By 19 months of age, she began experiencing both focal and generalized seizures occurring up to 4 times daily over a 2-month period, ultimately leading to hospitalization. An EEG performed at this time demonstrated epileptiform discharges in the right central, right temporal, and left temporal head regions. Antiepileptic therapies were initiated, with lack of response to phenobarbital and oxcarbazepine, with intolerable side effects to lacosamide. At 20 months of age, regression of skills with worsening language and motor delays and recurrent hand flapping, prompted a titration of previous medications and initiation of clobazam. A brain MRI at this time demonstrated delayed myelination for age without other notable findings. Exam findings at this time included round hypotonic facies, coarse facial features, hypertelorism, arched eyebrows and long eyelashes.

Results: Seizures persisted and were pharmacoresistant in nature, thus exome sequencing with concurrent chromosomal microarray analysis were initiated at age 20-months. Testing resulted with an interstitial duplication of 565kb of DNA at 16p11.2 (29635211_30199713)x3 and a pathogenic variant in SCN2A c.2557C>T (R853W). The patient is now 3-years-old and continues to experience focal seizures, reflux, global developmental delay, and self-injurious behavior. A repeat brain MRI revealed progressive volume loss within the supratentorial brain.

Discussion: This is the first reported case of patient with co-occurring16p11.2 duplication and a heterozygous SCN2A pathogenic variant. It is suspected that much of this patient’s phenotype is caused by the SCN2A variant. As a neurodevelopmental risk loci, the 16p11.2 duplication may increase this patient’s risk for more severe developmental delays, autism, or additional seizures types. Seizure control and early intervention therapies continue to be the mainstays of intervention to improve developmental outcomes, as to date there are no targeted anti-epileptic medications or other precision therapies for SCN2A-DEE.