Novel DOCK7 mutations in a Chinese patient with early infantile epileptic encephalopathy 23
Early infantile epileptic encephalopathy (EIEE) is a group of rare, devastating disorders that strike infants in their first year, causing uncontrolled seizures, delayed development, and lifelong disability. One subtype—EIEE23 (OMIM #615859)—affects fewer than 1 in a million people worldwide, but its genetic and clinical complexity has left many questions unanswered. Now, researchers from China and the U.S. have identified two new mutations in the DOCK7 gene linked to EIEE23, offering fresh insights into how this gene’s malfunction disrupts brain development.
In a 2019 study published in the Chinese Medical Journal, a team led by Bing Bai (Department of Pediatrics, First People’s Hospital of Yunnan Province) and Bao-Sheng Zhu (Kunming University of Science and Technology) described a 3-year-old Chinese girl with EIEE23. The child was the firstborn of healthy, non-related parents; her pregnancy was uneventful except for progesterone to prevent miscarriage, and she was born full-term at 2800g (within normal range for Chinese infants). But by 6 months, she developed daily infantile spasms (20 times a day) and showed clear signs of delayed development: she could sit and crawl but couldn’t walk stably or speak. She also had no reaction to her name—even though her hearing was normal—and struggled with daily tasks.
Her brain MRI revealed key abnormalities: a thin corpus callosum (the “bridge” between brain hemispheres), mild pontine hypoplasia (underdeveloped brainstem), dilated lateral ventricles, and pachygyria (fewer, wider brain folds). Eye exams confirmed cortical blindness (vision loss from brain damage, not eye issues) with horizontal nystagmus (involuntary eye movements) and left strabismus (crossed eye). Flash-evoked visual potentials (tests of brain response to light) showed delayed signals in her right eye and weak signals in both. She also had distinctive facial features: a low posterior hairline, protruding ears, a highly arched palate, and periorbital fullness (round, full eyelids). An atrial septal defect (hole in the heart) was another unique finding—never reported in previous EIEE23 cases.
Metabolic tests (blood amino acids, urine organic acids) and genetic screening (karyotype, array CGH) were normal, so the team turned to exome sequencing—a technique that reads the protein-coding parts of DNA. They sequenced the girl’s DNA and her parents’ and found two compound heterozygous mutations in the DOCK7 gene:
- c.C2479T: A “stop-gain” mutation that cuts the DOCK7 protein short in the TACC3-binding region (critical for brain cell development).
- c.5929-1G>C: A splice-site mutation that disrupts how the DOCK7 gene is edited into RNA, breaking the protein’s catalytic DHR2 domain (needed for axon growth).
Both mutations are “loss-of-function”—meaning they disable the DOCK7 protein. They were not found in public databases (1000 Genomes Project, gnomAD), confirming they are new. Evolutionary analysis showed the mutation sites are highly conserved across 17 vertebrates—proof they’re essential for DOCK7’s job.
Why does this matter? DOCK7 is a “guanine nucleotide exchange factor” (GEF) that helps neurons grow axons (long projections that send signals) and establish polarity (proper structure). It also interacts with the TACC3 protein to control neurogenesis—the process of making new brain cells. The girl’s mutations hit two critical parts of DOCK7: the TACC3-binding region (stopping brain cell production) and the DHR2 domain (halting axon growth). This disruption likely caused her seizures, developmental delays, and cortical blindness.
When the team compared their patient to the only three EIEE23 cases previously reported (by Perrault et al. in 2014), they found clear similarities: early seizures, hypsarrhythmia (chaotic brain waves), and MRI abnormalities like a thin corpus callosum. But there were key differences too: their patient had a low posterior (not anterior) hairline, pachygyria, no occipital lobe atrophy, and an atrial septal defect. These variations highlight EIEE23’s high genetic and phenotypic heterogeneity—meaning even patients with the same gene mutation can have different symptoms.
The study’s findings are a big step forward for EIEE23 research. Before this, only one paper had reported DOCK7 mutations in EIEE23. Now, with two new mutations, scientists have a broader understanding of how DOCK7 malfunction causes disease. This could help with genetic counseling (identifying at-risk families) and future gene therapy (targeting DOCK7 to restore brain development).
The team obtained full consent from the girl’s guardians to share her clinical data and images. The study was funded by the China Postdoctoral Science Foundation and Yunnan’s Health Technology Commission. No conflicts of interest were reported.
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doi.org/10.1097/CM9.0000000000000100
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