Submission Details

Variants in the CUL3 gene were first reported in individuals with complex neurodevelopmental disorder in 2012 (O'Roak et al., PMID 22495309; Kong et al., PMID 22914163). The gene-disease relationship was originally suggested by large cohort studies focusing on autism spectrum disorder, developmental delay, and intellectual disability (O'Roak et al., PMID 22495309; McRae et al., PMID 28135719; Stessman et al., PMID: 28191889). In addition to these features, other variable clinical features may include seizures, congenital heart defects, skeletal anomalies, and dysmorphic facial features (Thiffault et al., PMID 30311385; Nakashima et al., PMID 32341456). The phenotypic spectrum is still emerging as most reported patients were part of large cohort studies where only neurodevelopmental phenotypes were described. More than 30 truncating and missense variants in CUL3 have been documented in 15 publications, with the majority being de novo. Of note, we did not score any variants documented to be inherited from a parent, due to incomplete information about the affected status of the parents in large cohort studies. CUL3 is highly intolerant to loss of function variants (pLI=1) and highly constrained for missense variants (Z score=4.75) according to gnomAD v2.1.1. Evidence supporting this gene-disease relationship also includes experimental data. Three independent studies in heterozygous constitutive or conditional knockout mouse models showed behavioral abnormalities, including social and cognitive deficits, altered neuronal excitability, and defective cortical neuronal migration (Rapanelli et al., PMID 31455858; Dong et al., PMID 31780330; Morandell et al., doi: https://doi.org/10.1101/2020.01.10.902064). CUL3 encodes a E3 ubiquitin ligase and has been demonstrated to interact with RHOBTB2, KLHL15, and LZTR1 (Wilkins et al., PMID 15107402; Ferretti et al., PMID 27561354; Abe et al., PMID 31337872), which are implicated in neurodevelopmental disorders. Of note, variants in CUL3 leading to exon 9 skipping exert a dominant-negative effect and are associated with a different disorder, autosomal dominant pseudohypoaldosteronism type II, characterized by hypertension, hyperkalaemia, metabolic acidosis and normal renal function (OMIM #614496). In summary, CUL3 is definitively associated with complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/04/20 (SOP Version 8).