Novel DOCK7 Mutations in a Chinese Patient with Early Infantile Epileptic Encephalopathy 23

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Novel DOCK7 Mutations in a Chinese Patient with Early Infantile Epileptic Encephalopathy 23

Early infantile epileptic encephalopathy 23 (EIEE23) is a rare autosomal recessive disorder characterized by severe neurological impairments, including intractable seizures, psychomotor developmental delays, cortical blindness, and structural brain abnormalities. Caused by mutations in the DOCK7 gene, EIEE23 has been documented in only a handful of cases worldwide. This report presents the clinical and genetic findings of a Chinese patient with EIEE23 harboring novel compound heterozygous mutations in DOCK7, expanding the mutational and phenotypic spectrum of this devastating condition.

Clinical Presentation and Diagnostic Evaluation

The patient, a 3-year-old Chinese female, was born to non-consanguineous parents after an uneventful pregnancy, except for progesterone supplementation to prevent miscarriage. Her birth weight (2800 g) fell within the normal range for China (2500–4000 g). Neonatal screening revealed an atrial septal defect, but no other immediate complications. At 6 months of age, she developed infantile spasms, manifesting as head nodding episodes occurring approximately 20 times daily. Concurrently, she exhibited global developmental delays, hypotonia, and an inability to communicate verbally. By 20 months, electroencephalography (EEG) revealed hypsarrhythmia and multifocal sharp waves localized to the parietotemporal cortex.

Brain magnetic resonance imaging (MRI) at age 3 demonstrated multiple structural anomalies: an abnormally prominent pontobulbar sulcus (Figure 1A), mild pontine hypoplasia (Figure 1B), thinning of the corpus callosum with lateral ventricular dilation (Figure 1C), and pachygyria (Figure 1D). Ophthalmological evaluations confirmed cortical blindness, evidenced by horizontal nystagmus, left strabismus, and abnormal flash-evoked visual potentials (FEVP) showing prolonged latency in the right eye and reduced amplitudes bilaterally. Dysmorphic facial features included low posterior hairlines, protruding ears, a highly arched palate, gingival maldevelopment, and periorbital fullness. Metabolic screenings, karyotyping, and chromosomal microarray analysis (CytoScan) yielded normal results, excluding other etiologies.

Genetic Analysis and Mutation Identification

Whole-exome sequencing (WES) of the proband and her unaffected parents identified two novel compound heterozygous mutations in DOCK7 (NM_001271999): a splice-site variant (c.5929-1G>C) and a nonsense variant (c.C2479T, p.R827X). Sanger sequencing confirmed both mutations’ presence in the proband and their heterozygous carrier status in the parents.

The c.C2479T (p.R827X) mutation in exon 21 introduces a premature stop codon within the TACC3-binding (T-b) region (amino acids 506–1164), a critical domain for DOCK7’s interaction with TACC3 during cortical neurogenesis. The c.5929-1G>C variant disrupts the canonical splice donor site of exon 46, located within the DHR2 domain (amino acids 1678–2114), which is essential for DOCK7’s guanine nucleotide exchange factor (GEF) activity. Evolutionary conservation analysis across 17 vertebrate species confirmed both mutation sites reside in highly conserved regions, underscoring their functional significance. These loss-of-function (LOF) mutations are absent from public variant databases (1000 Genomes, ExAC, ClinVar), supporting their pathogenicity.

Functional Implications of DOCK7 Mutations

DOCK7 regulates neuronal polarization, axonogenesis, and progenitor differentiation via its DHR1, DHR2, and T-b domains. The DHR2 domain activates Rac1/Rac3 GTPases, which orchestrate cytoskeletal dynamics by phosphorylating stathmin (STMN1) to stabilize nascent axons. The T-b region mediates interactions with TACC3, modulating interkinetic nuclear migration (INM) to balance neuronal progenitor self-renewal and differentiation.

The p.R827X truncation eliminates most of the T-b region, likely disrupting DOCK7-TACC3 binding and impairing neurogenesis. The c.5929-1G>C splice-site mutation is predicted to cause exon skipping or intron retention, abolishing DHR2-mediated Rac activation. Together, these mutations destabilize cortical development, leading to aberrant neuronal migration (pachygyria), axonal guidance defects (thin corpus callosum), and impaired cortical organization—consistent with the patient’s structural brain anomalies and seizures.

Comparative Analysis with Previously Reported Cases

Three EIEE23 cases were previously described by Perrault et al. (2014), all sharing core features: infantile spasms, hypsarrhythmia, cortical blindness, and pontocerebellar abnormalities. Table 1 contrasts these cases with the current patient, highlighting shared and distinct characteristics.

Shared Features:

  • Seizure Onset: All patients developed seizures between 2–6 months, with hypsarrhythmia on EEG.
  • Neurodevelopmental Delays: Severe motor and speech impairments were universal; the proband could walk unsteadily but lacked verbal communication.
  • Cortical Blindness: Absent visual fixation and abnormal FEVP findings were consistent across cases.
  • Pontocerebellar Abnormalities: MRI revealed pontobulbar sulcus prominence and pontine hypoplasia in all patients.

Distinct Features:

  • Structural Brain Anomalies: The current patient exhibited pachygyria and lateral ventricular dilation, unlike the occipital atrophy seen in prior cases.
  • Dysmorphism: Unique features included low posterior hairlines, gingival maldevelopment, and strabismus, differing from the telecanthus and anteverted nares reported earlier.
  • Cardiac Defect: An atrial septal defect was noted here but not in previous cases, suggesting potential pleiotropic effects of DOCK7 mutations.

Broader Implications for EIEE23 Diagnosis and Management

This case underscores the phenotypic heterogeneity of EIEE23 and expands the known mutational spectrum of DOCK7. The identification of LOF mutations in both alleles reinforces DOCK7’s causative role in EIEE23. Clinically, this highlights the importance of WES in diagnosing enigmatic neurodevelopmental disorders, particularly when metabolic and cytogenetic tests are unrevealing.

The patient’s unique features—pachygyria, cardiac defect, and distinct dysmorphism—suggest that DOCK7 mutations may affect broader developmental pathways beyond neurogenesis. Further studies are needed to explore DOCK7’s roles in cardiac development and craniofacial morphogenesis.

Conclusion

This report describes novel compound heterozygous DOCK7 mutations (c.5929-1G>C and c.C2479T) in a Chinese patient with EIEE23, characterized by infantile spasms, cortical blindness, and structural brain anomalies. The mutations disrupt critical functional domains, impairing neuronal polarization and cortical development. By delineating unique clinical features, this study enhances understanding of EIEE23’s phenotypic variability and provides a foundation for future functional studies and therapeutic strategies.

https://doi.org/10.1097/CM9.0000000000000100

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