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.