CUL3 – Neurodevelopmental Disorder with or without Autism or Seizures

CUL3 encodes the scaffold subunit of Cullin-RING E3 ubiquitin ligase complexes and is essential for proteasomal degradation of key neurodevelopmental substrates. Heterozygous variants in CUL3 have been identified in 28 unrelated individuals presenting with global developmental delay, speech impairment, autistic features, and seizures, establishing a strong role for CUL3 haploinsufficiency in this neurodevelopmental disorder ([PMID:39501558]; [PMID:37026922]; [PMID:40176836]).

Genetic evidence includes autosomal dominant inheritance of de novo and familial truncating, splice-site, and missense variants, consistent with a loss-of-function mechanism. In a cohort of 26 patients carrying pathogenic or likely pathogenic CUL3 variants, DNA methylation profiling revealed a sensitive and specific episignature that distinguished affected individuals from controls and reclassified VUS ([PMID:39501558]). Two additional case reports describe a nonsense variant c.2065A>T (p.Lys689Ter) in a Chinese patient and a de novo missense variant c.368T>A (p.Leu123Gln) in a Turkish child, both with epilepsy and autistic features ([PMID:37026922]; [PMID:40176836]).

Functional studies support haploinsufficiency as the pathogenic mechanism. Knockout of CUL3 in human iPSC-derived cortical neurons leads to delayed transition from neural progenitors to postmitotic neurons and reduced network activity, implicating impaired neurogenesis ([PMID:32890664]). A haploinsufficient mouse model exhibits cytoskeletal defects, reduced dendritic arborization, and hypoactivity rescued by RhoA inhibition, linking CUL3 loss to disrupted RhoA signaling in cortical development ([PMID:33727673]).

No conflicting evidence disputing the CUL3–neurodevelopmental disorder association has been reported. Overall, the convergence of robust genetic, epigenomic, and cellular phenotypes supports a Strong clinical validity classification for CUL3 in neurodevelopmental disorder with or without autism or seizures.

Key Take-home: Heterozygous CUL3 loss-of-function variants cause an autosomal dominant neurodevelopmental syndrome characterized by developmental delay, autistic behaviors, and epilepsy, diagnosable by genetic testing and DNA methylation episignature.

References

• American Journal of Human Genetics • 2023 • Neurodevelopmental disorder with or without autism or seizures is caused by CUL3 haploinsufficiency PMID:39501558
• Medicine • 2023 • A nonsense mutation in the CUL3 gene in a Chinese patient with autism spectrum disorder and epilepsy: A case report. PMID:37026922
• Molecular Syndromology • 2025 • Discovery of a Novel CUL3 Variant: Unveiling Epilepsy and Newly Associated Dysmorphic Traits in a Turkish Patient. PMID:40176836
• Neuroscience • 2020 • Loss-of-function Mutations of CUL3, a High Confidence Gene for Psychiatric Disorders, Lead to Aberrant Neurodevelopment In Human Induced Pluripotent Stem Cells. PMID:32890664
• Molecular Psychiatry • 2021 • Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling. PMID:33727673

Evidence Based Scoring (AI generated)