Abstracts

Rationale: Greater than fifty percent of epilepsy disorders are thought to have a genetic basis. While next-generation sequencing (NGS) panels are capable of identifying the causative mutation in an estimated 20-25% of pediatric patients, many genetic epilepsy disorders are quite rare, and the associated genes are often not included on NGS panels. Whole exome sequencing (WES) can be helpful in identifying the causative mutation in families with a suspected genetic etiology, for whom panels and/or microarray testing have been non-diagnostic. Methods: A family with three similarly affected children presented to the Neurogenetics Clinic at Children's Hospital Colorado. Prior genetic and biochemical workup had been unremarkable. Clinical whole exome sequencing was performed for all three affected siblings and their asymptomatic mother. Results: Three siblings (two male and one female) presented with intractable epileptic encephalopathy, cortical visual impairment, structrual brain abnormalities, and dysmorphic facial features. An epilepsy panel, microarray, and extensive biochemical testing had been non-diagnostic. The patients' mother, father, and two additional siblings were unaffected, suggesting an autosomal recessive pattern of inheritance.Clinical exome sequencing revealed compound heterozygous variants in the DOCK7 gene in all three affected siblings. The first is a maternally inherited pathogenic nonsense variant (c.4045C>T; p.R1349*) resulting in premature protein truncation. The second is a likely pathogenic variant (c.3843G>A; p.T1281T) which occurs in the last nucleotide of exon 30, and is predicted to disrupt the canonical splice donor site. This variant is presumably paternally inherited, given its presence in all three siblings. Confirmatory testing for the patients’ father is currently pending.The protein encoded by the DOCK7 gene, dedicator of cytokinesis 7, is a guanine nucleotide exchange factor which plays a role in axon formation and neuronal polarization. Pathogenic variants in DOCK7 have previously been described in three individuals from two unrelated, non-consanguineous families, all of whom present very similarly to our patients, with early onset epileptic encephalopathy, cortical visual impairment, global developmental delays, and dysmorphic features. MRI findings for these patients included mild pontine hypoplasia, hypoplasia of the corpus callosum, and T2 hyperintensities with atrophy in the occipital white and gray matter. Our patients exhibited some of these findings (T2 hyperintesities and pontine hypoplasia), but also showed additional structural abnormalities, including temporo-occipital cortical dysplasia, hippocampal sclerosis, mesial temporal sclerosis, and temporal and occipital horn gray matter heterotopia. Conclusions: The identification of compound heterozygous DOCK7 variants in this family will double the number of patients described in the literature with this disorder. This case report further demonstrates the association of DOCK7 with epileptic encephalopathy, cortical visual impairment, and a recognizable pattern of dysmorphic features, and also expands the spectrum of MRI abnormalities that may be observed in this condition. Whole exome sequencing is a powerful tool that can help to end the diagnostic odyssey for patients with rare epilepsy disorders and to expand our knowledge of these rare genetic conditions. Funding: None