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Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.

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Genetic variants in the DOCK4 gene are linked to a novel neurodevelopmental disorder. This condition is characterized by developmental delays, microcephaly, and impaired neurite outgrowth in affected individuals.

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Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Neurons are fundamental to the nervous system; their differentiation and neurite formation are crucial for development.
  • Cytoskeletal dynamics are vital for neuronal development, regulated by proteins like dedicator of cytokinesis 4 (DOCK4).
  • DOCK4 activates RAC1, playing a role in cellular processes essential for neuronal structure.

Purpose of the Study:

  • To clinically characterize individuals with DOCK4 variants and identify associated neurodevelopmental phenotypes.
  • To investigate the molecular and functional impact of DOCK4 variants on neurite outgrowth.
  • To establish DOCK4 loss-of-function variants as a probable cause of a novel neurodevelopmental disorder.

Main Methods:

  • Clinical assessment of 7 individuals (6 males, 1 female) with DOCK4 variants.
  • Molecular modeling to analyze the structural impact of missense variants.
  • In vitro functional studies using Neuro-2A cells, including missense variant expression and DOCK4 knockout models.

Main Results:

  • Individuals presented with global developmental delay, microcephaly, coordination issues, hypotonia, and seizures.
  • Molecular modeling indicated missense variants often disrupt DOCK4's globular structure.
  • Functional studies confirmed that DOCK4 variants impair neurite outgrowth in vitro.

Conclusions:

  • Loss-of-function variants in DOCK4 are strongly associated with a spectrum of neurodevelopmental disorders.
  • The findings highlight DOCK4's critical role in human neurodevelopment.
  • This study identifies a novel microcephaly-associated neurodevelopmental disorder linked to DOCK4 dysfunction.