Characteristic facial features and cortical blindness distinguish the DOCK7‐related epileptic encephalopathy

Abstract Background The epileptic encephalopathies display extensive locus and allelic heterogeneity. Biallelic truncating DOCK7 variants were recently reported in five children with early‐onset epilepsy, intellectual disability, and cortical blindness, indicating that DOCK7 deficiency causes a specific type of epileptic encephalopathy. Methods We identified 23‐ and 27‐year‐old siblings with the clinical pattern reported for DOCK7 deficiency, and conducted genome‐wide linkage analysis and WES. The consequences of a DOCK7 variant were analyzed on the transcript and protein level in patients’ fibroblasts. Results We identified a novel homozygous DOCK7 frameshift variant, an intragenic tandem duplication of 124‐kb, previously missed by CGH array, in adult patients. Patients display atrophy in the occipital lobe and pontine hypoplasia with marked pontobulbar sulcus, and focal atrophy of occasional cerebellar folia is a novel finding. Recognizable dysmorphic features include normo‐brachycephaly, narrow forehead, low anterior and posterior hairlines, prominent ears, full cheeks, and long eyelashes. Our patients function on the level of 4‐year‐old children, never showed signs of regression, and seizures are largely controlled with multi‐pharmacotherapy. Studies of patients’ fibroblasts showed nonsense‐mediated RNA decay and lack of DOCK7 protein. Conclusion DOCK7 deficiency causes a definable clinical entity, a recognizable type of epileptic encephalopathy