A novel truncating mutation of DOCK7 gene with an early-onset non-encephalopathic epilepsy

What is the definition of non-encephalopathic epilepsy?

Dilsad Turkdogan.  A novel truncating mutation of  DOCK7 gene with an early-onset non-encephalopathic epilepsy.  Seizure: European Journal of Epilepsy.  In press.

DOCK7(MIM:615730) plays a key role in neurogenesis by promoting the differentiation and transition of radial glial cells to basal progenitors and neurons . DOCK7also regulates tangential neuroblast migration in the postnatal mouse forebrain .

Recently, a new phenotype of early infantile epileptic encephalopathies (EIEE23, MIM: 615859) was reported in 3 girls from 2 families with 4 different compound heterozygous truncating mutations in DOCK7. Here, we report a boy with infantile onset well-controlled non-encephalopathic epilepsy and severe neurodevelopmental delay associated with a novel homozygous truncating mutation in DOCK7…

They did not notice any issues regarding the neurological development of the baby until 3.5 months of age when he presented with a generalized tonic-clonic seizure evolving to status epileptics. Neurological examination showed severe neurodevelopmental delay and lack of eye contact…

He had frequent focal motor seizures which stopped after clobazam add on therapy at 13 months of age after being referred to our hospital and has been seizure free since then. Initial EEG examinations showed generalized sharp waves. Resolution of EEG progressively occurred: focal epileptiform discharges were recorded at 18 months of age and he has had normal EEG findings for the past 16 months…

Neurological examination currently shows delayed gross and fine motor functions(about at the developmental level of 15 and 8 months, respectively), lack of any visual contact with faces or objects, joint attention, social jests, or pretend play. He has intense mouthing objects. He notices the strangers and follows some simple verbal commands but no speech even vocalization is present.  Dysmorphic features include normo-brachycephaly, narrow forehead, low anterior hairline, wide and anteverted nasal tip, prominent ears, full cheeks, long eyelashes, smooth and short philtrum and thin upper lip.

Cranial MRI examination at 33 months of age showed an abnormally marked pontobulbar sulcus associated with pontine hypoplasia, a thin corpus callosum, absence of interventricular septum, slight interdigitation of gyri across the interhemispheric fissure, and atrophy in the white and gray matter of the occipital lobe with increased signal on both T2 and FLAIR images…

A novel homozygous nonsense variant (Chr 1: 63003683T&gt,A GRCh37/hg19, NM_033407: c.3257T&gt,A, NP_212132:p.Leu1086*) in exon 27 ofDOCK7was identified . The present variant confirmed by Sanger sequencing was not found in ESP, ExAC, 1000G, and gnomAD. His unaffected parents were heterozygous for this variant…

The present variant, classified as pathogenic according to ACMG criteria, leads to a premature stop codon and is predicted to result in a truncation of DOCK7 after 1086 of 2,109 amino acids and/or in nonsense-mediated mRNA decay (NMD). As a stop gain mutation locates in exon 27, post-transcriptional mRNA quality control mechanism (nonsense mediated decay) eliminates the mRNA of DOCK7 containing this premature termination codon. Similarly, the reported 4 compound heterozygote mutations are located in upstream exons, and are proposed as having the potential to induce nonsense-mediated decay of the corresponding mRNA .

Our patient gained some developmental skills with regard to motor and limited nonverbal interactions, but the presence of some autistic features and lack of verbal skills imply a specific clinical picture associated with truncating mutations of DOCK7 . The dysmorphic features and structural brain abnormalities are the main complementary findings of this rare entity. Contrary to 3 intractable EIEE patients firstly reported by Perrault et al., our patient presents a drug-responsive non-encephalopathic epilepsy despite remaining similar clinical features. However, we do not have the long-term prognosis of epilepsy in our case.