Novel DOCK7 mutations in a Chinese patient with early infantile epileptic encephalopathy 23

Abstract

To the Editor: Early infantile epileptic encephalopathy 23 (EIEE23; OMIM #615859) is a rare ( C, NM_001271999;c.C2479T; p.R827X; UCSC Genome Browser hg19 assembly) to be the most likely causative variants, which were confirmed by Sanger sequencing. The DHR1 domain, the catalytic DHR2 domain, and the TACC3 protein-interacting region (T-b region) are necessary for DOCK7 functionality in cortical neurogenesis, axon development, and neuronal polarity.[3–5] As shown in Figure 1E, variant c.C2479T is located in exon 21 (NM_001271999) and results in a premature stop codon in the anterior part of the T-b region (amino acids 506–1164).[3] The other variant c.5929-1G>C changes the first 5′ splice donor site (G) of exon 46 into C in the DHR2 domain (DOCK7 UniProt prediction amino acids Q96N67. 1678–2114). It is highly likely that these variants will lead to the premature decay of the corresponding mRNA, affect DOCK7's interaction with TACC3, and disable its DHR2 domain. We further showed through evolutionary conservation analyses that these 2 variant sites are highly conserved among 17 vertebrates [Figure 1E]. Both variants are loss-of-function (LOF) mutations and have never been reported in any public human genetic variant databases such as the 1000 Genomes Project, NHLBI/NIH Exome Sequencing Project, ExAC/gnomAD, ClinVar, or dbSNP. EIEE23 is a rare and extensively incapacitating disease with an early onset during infancy. Only 3 cases of this disease have been reported to date. Table…