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.
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: Elizabeth E Palmer; Kelsey E Jarrett; Rani K Sachdev; Fatema Al Zahrani; Mais Omar Hashem; Niema Ibrahim; Hugo Sampaio; Tejaswi Kandula; Rebecca Macintosh; Rajat Gupta; Donna M Conlon; Jeffrey T Billheimer; Daniel J Rader; Kouichi Funato; Christopher J Walkey; Chang Seok Lee; Christine Loo; Susan Brammah; George Elakis; Ying Zhu; Michael Buckley; Edwin P Kirk; Ann Bye; Fowzan S Alkuraya; Tony Roscioli; William R Lagor Journal: Hum Mol Genet Date: 2016-06-06 Impact factor: 6.150
Authors: Rebekkah J Hitti; James A C Oliver; Ellen C Schofield; Anina Bauer; Maria Kaukonen; Oliver P Forman; Tosso Leeb; Hannes Lohi; Louise M Burmeister; David Sargan; Cathryn S Mellersh Journal: Genes (Basel) Date: 2019-05-21 Impact factor: 4.096
Authors: Perunthottathu K Umasankar; Li Ma; James R Thieman; Anupma Jha; Balraj Doray; Simon C Watkins; Linton M Traub Journal: Elife Date: 2014-10-10 Impact factor: 8.140