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Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.

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This study identifies new CUL3 gene variants causing neurodevelopmental disorders (NDDs). Loss-of-function variants disrupt protein stability and homeostasis, impacting intellectual disability and autistic features in affected individuals.

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Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • De novo variants in cullin-3 ubiquitin ligase (CUL3) are linked to neurodevelopmental disorders (NDDs).
  • Limited large-scale case series exist for CUL3-associated NDDs.
  • Understanding genotype-phenotype correlations and pathogenic mechanisms is crucial.

Purpose of the Study:

  • To collect and analyze sporadic cases with rare CUL3 variants.
  • To describe the genotype-phenotype correlation in individuals with CUL3 variants.
  • To investigate the underlying pathogenic mechanisms of CUL3-associated NDDs.

Main Methods:

  • Multicenter collaboration for genetic data and clinical records.
  • Dysmorphic facial features analyzed using GestaltMatcher.
  • Assessment of CUL3 protein stability using patient-derived T-cells.

Main Results:

  • A cohort of 37 individuals with heterozygous CUL3 variants and syndromic NDD was assembled.
  • 35 individuals had loss-of-function (LoF) variants, and 2 had missense variants.
  • CUL3 LoF variants may impair protein stability and homeostasis, evidenced by reduced ubiquitin-protein conjugates and impaired proteasomal degradation of the substrate 4E-BP1.

Conclusions:

  • This study refines the clinical and mutational spectrum of CUL3-associated NDDs.
  • It expands the range of neuropsychiatric disorders linked to cullin RING E3 ligases.
  • Haploinsufficiency due to LoF variants appears to be the primary pathogenic mechanism.