CUL3

Inheritance Pattern: AD

Disease ID:MONDO:0030994

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0013782

Submitter: ClinGen

The *CUL3* gene is located on chromosome 2 at q36.2 and encodes cullin-3, a scaffolding component of the Cullin-RING ligase (CRL) complex that belongs to a class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins destined for degradation. E3 ligases containing CUL3 interact with KLHL3 and are involved in controlling blood pressure in the body by regulating the amount of WNK1 and WNK4 available. *CUL3* mutation was first reported in relation to autosomal dominant Pseudohypoaldosteronism, type II (PHA2E) in 2012 (Boyden et al., PMID: 22266938). This disorder is also known as Gordon syndrome, and familial hyperkalemic hypertension. The preferred disease name suggested for this disorder is ‘Familial hypertension with hyperkalaemia - CUL3’. The disorder is characterized by hyperkalemia, hypertension, metabolic acidosis and suppressed plasma renin levels despite a normal glomerular filtration rate. *CUL3* mutation has also been associated with autosomal dominant Neurodevelopmental disorder with or without autism or seizures. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, although both conditions have an AD inheritance, there is a difference in molecular mechanism and in clinical phenotype. Therefore, the following disease entities have been split into two distinct disease entities: Pseudohypoaldosteronism, type IIE (OMIM:614496) and Neurodevelopmental disorder with or without autism or seizures (OMIM:619239). Autosomal dominant Neurodevelopmental disorder with or without autism or seizures has been curated separately by the ID/Austim GCEP on 1/16/2021. Nine variants (intronic, canonical splice, splice donor, splice acceptor, splice enhancer) that have been reported in 8 probands in 4 publications (PMIDs: 22266938, 24266877, 29511623, 34480842) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by expression studies, protein interaction studies, and mouse models. (PMIDs: 29869755, 26286618). In summary, *CUL3* is definitively associated with autosomal dominant familial hypertension with hyperkalaemia - CUL3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0030994

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0013782

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013782

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013782

Submitter: Ambry Genetics