Epileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically. To describe a multiplex extended consanguineous family that defines a molecularly novel subtype of early infantile epileptic encephalopathy. Autozygosity mapping and exome sequencing for the identification of the causal mutation. This was followed by expression analysis of the candidate gene. In an extended multigenerational family with six affected individuals, a single novel disease locus was identified on chromosome 12p13.31-p13.2. Within that locus, the only deleterious novel exomic variant was a homozygous truncating mutation in NECAP1, encoding a clathrin-accessory protein. The mutation was confirmed to trigger nonsense-mediated decay. Consistent with previous reports, we show that NECAP1 is highly enriched in the central nervous system. NECAP1 is known to regulate clathrin-mediated endocytosis in synapses. The mutation we report here links for the first time this trafficking pathway in early infantile epileptic encephalopathy.