ORPHA: 528084;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q36.2 | Neurodevelopmental disorder with or without autism or seizures | 619239 | Autosomal dominant | 3 | CUL3 | 603136 |
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with or without autism or seizures (NEDAUS) is caused by heterozygous mutation in the CUL3 gene (603136) on chromosome 2q36.
Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is characterized by global developmental delay apparent in infancy, impaired intellectual development, and speech delay. Some patients develop seizures, and may show regression after onset of seizures. Others have autistic features or behavioral abnormalities. Additional variable systemic features may also be present, such as cardiac defects, failure to thrive, or brain imaging anomalies (summary by Nakashima et al., 2020).
Thiffault et al. (2018) reported a 3-year-old boy (family 2) with failure to thrive, microcephaly, speech delay, and absent thumb associated with a de novo mutation in the CUL3 gene. He was ascertained from a large cohort of patients with neurodevelopmental disorders who underwent next-generation sequencing and were found to have de novo variants in various genes. Clinical details were limited.
Da Silva Montenegro et al. (2020) reported a 12-year-old Brazilian girl (F1389-1) with NEDAUS. She had mild motor delay, speech delay, and autism spectrum disorder. She did not have seizures.
Nakashima et al. (2020) reported 3 unrelated children, ranging from 3 to 10 years of age, with a neurodevelopmental disorder. Two patients (patients 1 and 2), of Japanese and Malaysian origin, respectively, were ascertained from a large cohort of 1,230 individuals with early childhood-onset epilepsy who underwent whole-exome sequencing. Patient 3 was identified through the GeneMatcher program. Patients 1 and 2 had onset of intractable spasms and seizures at 2 and 6 months of age, respectively. EEG in patient 1 showed a suppression-burst pattern, whereas EEG in patient 2 showed hypsarrhythmia, both consistent with a clinical diagnosis of West syndrome. They had delayed motor development and severe intellectual disability with speech delay. Patient 2 had hyperactivity; patient 1 had an atrial septal defect and pulmonary valve stenosis. Patient 3 had poor feeding and mildly delayed psychomotor development with speech delay. Brain imaging showed delayed subcortical myelination. She did not have facial dysmorphism, but did have submucosal palatoschisis and bifid uvula. None of the patients was noted to have autism.
Iwafuchi et al. (2021) reported a 4-year-old Japanese girl with poor overall growth who presented at age 21 months with status epilepticus after normal early development. After seizure onset, she showed developmental regression with loss of speech and loss of eye contact. She later developed behavioral abnormalities consistent with autism spectrum disorder and reminiscent of Rett syndrome (RTT; 312750).
The heterozygous mutations in the CUL3 gene that were identified in patients with NEDAUS by Nakashima et al. (2020) occurred de novo.
In a 3-year-old boy (family 2) with NEDAUS, Thiffault et al. (2018) identified a de novo heterozygous missense mutation in the CUL3 gene (Y58C; 603136.0008). The mutation, which was found by trio-based next-generation sequencing, was considered to be pathogenic after curation using a point-based system. Functional studies of the variant were not performed. The authors noted that several large studies had identified de novo mutations in the CUL3 gene in patients with variable neurodevelopmental disorders. For example, Kong et al. (2012) identified a de novo heterozygous loss-of-function R546X variant in 1 of 44 Icelandic individuals with autism spectrum disorder.
In a 12-year-old Brazilian girl (F1389-1) with NEDAUS, da Silva Montenegro et al. (2020) identified a de novo heterozygous nonsense mutation in the CUL3 gene (S133X; 603136.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was classified as pathogenic according to ACMG criteria.
In 3 unrelated children with NEDAUS, Nakashima et al. (2020) identified de novo heterozygous mutations in the CUL3 gene (603136.0010-603136.0012). There were 2 frameshift mutations and 1 missense mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the dbSNP (build 153) or gnomAD databases. All were predicted or demonstrated to result in a loss of function and haploinsufficiency. Two patients were ascertained from a cohort of 1,230 individuals with childhood-onset epilepsy who underwent whole-exome sequencing; the third patient was identified through the GeneMatcher program.
In a 4-year-old Japanese girl with NEDAUS, Iwafuchi et al. (2021) identified a de novo heterozygous frameshift mutation in the CUL3 gene (603136.0013). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to lead to nonsense-mediated mRNA decay and haploinsufficiency. Functional studies of the variant were not performed.
Dong et al. (2020) found that mice with homozygous deletion of Cul3 had reduced body size and brain weight compared with wildtype, and died prematurely. Mice heterozygous for Cul3 deletion (Cul3-deficient mice) had more than 40% reduced levels of Cul3, but were viable and fertile, survived as long as wildtype, and did not show deficits observed in mice with homozygous Cul3 deletion. Cul3-deficient mice exhibited social behavioral deficits and anxiety-like behaviors. Hippocampus of Cul3-deficient mice had increased spine density, neuronal excitability, and synaptic transmission and disrupted excitation-inhibition (E-I) balance in CA1 neurons. Similar deficits were observed in pyramidal neurons with Cul3 deficiency, demonstrating a cell-autonomous role of Cul3 for synaptic function, E-I balance, and behavior. Proteomic analysis identified Eif4g1 (600495) as a target of Cul3-dependent ubiquitination. Consequently, Cul3 deficiency increased Eif4g1 level and upregulated Cap-dependent protein synthesis in brain. Inhibition of Cap-dependent translation diminished synaptic and social deficits in Cul3-deficient mice, but it had little effect on anxiety-like behaviors. However, chemogenetic inhibition of pyramidal neuron activity in hippocampus attenuated anxiety-like behavior in mutant mice.
da Silva Montenegro, E. M., Costa, C. S., Campos, G., Scliar, M., de Almeida, T. F., Zachi, E. C., Silva, I. M. W., Chan, A. J. S., Zarrei, M., Lourenco, N. C. V., Yamamoto, G. L., Scherer, S., Passos-Bueno, M. R. Meta-analyses support previous and novel autism candidate genes: outcomes of an unexplored Brazilian cohort. Autism Res. 13: 199-206, 2020. [PubMed: 31696658] [Full Text: https://doi.org/10.1002/aur.2238]
Dong, Z., Chen, W., Chen, C., Wang, H., Cui, W., Tan, Z., Robinson, H., Gao, N., Luo, B., Zhang, L., Zhao, K., Xiong, W.-C., Mei, L. CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance through the promotion of Cap-dependent translation. Neuron 105: 475-490, 2020. [PubMed: 31780330] [Full Text: https://doi.org/10.1016/j.neuron.2019.10.035]
Iwafuchi, S., Kikuchi, A., Endo, W., Inui, T., Aihara, Y., Satou, K., Kaname, T., Kure, S. A novel stop-gain CUL3 mutation in a Japanese patient with autism spectrum disorder. Brain Dev. 43: 303-307, 2021. [PubMed: 33097317] [Full Text: https://doi.org/10.1016/j.braindev.2020.09.015]
Kong, A., Frigge, M. L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S. A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Wong, W. S. W., Sigurdsson, G., and 9 others. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488: 471-475, 2012. [PubMed: 22914163] [Full Text: https://doi.org/10.1038/nature11396]
Nakashima, M., Kato, M., Matsukura, M., Kira, R., Ngu, L.-H., Lichtenbelt, K. D., van Gassen, K. L. I., Mitsuhashi, S., Saitsu, H., Matsumoto, N. De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms. J. Hum. Genet. 65: 727-734, 2020. [PubMed: 32341456] [Full Text: https://doi.org/10.1038/s10038-020-0758-2]
Thiffault, I., Cadieux-Dion, M., Farrow, E., Caylor, R., Miller, N., Soden, S., Saunders, C. On the verge of diagnosis: detection, reporting, and investigation of de novo variants in novel genes identified by clinical sequencing. Hum. Mutat. 39: 1505-1516, 2018. [PubMed: 30311385] [Full Text: https://doi.org/10.1002/humu.23646]