NECAP1 loss of function leads to a severe infantile epileptic encephalopathy

BACKGROUND: Epileptic encephalopathy is a broad clinical category that is highly heterogeneous genetically. OBJECTIVE: To describe a multiplex extended consanguineous family that defines a molecularly novel subtype of early infantile epileptic encephalopathy. METHODS: Autozygosity mapping and exome sequencing for the identification of the causal mutation. This was followed by expression analysis of the candidate gene. RESULTS: 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. CONCLUSIONS: 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.