title: NECAP1 loss of function leads to a severe infantile epileptic encephalopathy.
abstract: 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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.forename: Hadia
authors.initials: H
authors.lastname: Hijazi
authors.forename: Amal Y
authors.initials: AY
authors.lastname: Kentab
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D033965:Adaptor Protein Complex alpha Subunits / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D005190:Family; D017809:Fatal Outcome; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: D033965:Adaptor Protein Complex alpha Subunits; D008565:Membrane Proteins; C000592908:NECAP1 protein, human; C000592909:NECAP1 protein, mouse
keywords: Clathrin; Encephalopathy; Neuron; Synapse; Vesicle