Human Gene Module / Chromosome 2 / CUL3

CUL3Cullin 3

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
17 / 26
Rare Variants / Common Variants
44 / 1
EAGLE Score
18.4
Strong Learn More
Aliases
CUL3, CUL-3,  PHA2E
Associated Syndromes
-
Chromosome Band
2q36.2
Associated Disorders
ID, EPS
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Relevance to Autism

Two de novo loss-of-function (LoF) mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

Molecular Function

This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation.

SFARI Genomic Platforms
Reports related to CUL3 (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics Bennett EJ , et al. (2010) No -
2 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
3 Support Rate of de novo mutations and the importance of father's age to disease risk Kong A , et al. (2012) Yes -
4 Recent Recommendation Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases Canning P , et al. (2013) No -
5 Recent Recommendation Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4 Shibata S , et al. (2013) No -
6 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
8 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders Codina-Sol M , et al. (2015) Yes -
9 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
10 Recent Recommendation Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor McGourty CA , et al. (2016) No -
11 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
12 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
13 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
14 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
15 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
16 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
17 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
18 Support Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans Wong WR , et al. (2019) Yes -
19 Support Cul3 and insomniac are required for rapid ubiquitination of postsynaptic targets and retrograde homeostatic signaling Kikuma K , et al. (2019) No -
20 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
21 Support Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort da Silva Montenegro EM , et al. (2019) Yes -
22 Support De novo variants in CUL3 are associated with global developmental delays with or without infantile spasms Nakashima M et al. (2020) No ID, epilepsy/seizures
23 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
24 Support - Morandell J et al. (2021) Yes -
25 Support - Mahjani B et al. (2021) Yes -
26 Support - Li D et al. (2022) Yes -
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 27841880 Redin C , et al. (2016)
c.571G>T p.Glu191Ter stop_gained Unknown - - 34968013 Li D et al. (2022)
c.614C>G p.Ser205Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.757C>T p.Arg253Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1654C>T p.Arg552Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1008+1G>T - splice_site_variant De novo NA - 33004838 Wang T et al. (2020)
c.1669C>A p.Pro557Thr missense_variant Unknown - - 34968013 Li D et al. (2022)
c.185G>A p.Arg62His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.245G>A p.Arg82Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1636C>T p.Arg546Ter stop_gained De novo NA - 22914163 Kong A , et al. (2012)
c.320T>C p.Phe107Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.475C>T p.Arg159Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1327G>A p.Ala443Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1802C>T p.Ser601Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2110G>A p.Asp704Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
T>C p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK et al. (2017)
c.67-22145del - frameshift_variant De novo NA - 32341456 Nakashima M et al. (2020)
c.1046A>G p.Gln349Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.793G>T p.Glu265Ter splice_site_variant De novo NA - 27824329 Wang T , et al. (2016)
c.854T>C p.Val285Ala missense_variant De novo NA - 32341456 Nakashima M et al. (2020)
c.736G>T p.Glu246Ter stop_gained De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.541C>T p.Arg181Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1644+2T>C - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.67-22109A>G - missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.521del p.Met174ArgfsTer11 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1595dup p.Ala533SerfsTer7 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1961C>T p.Pro654Leu missense_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.917del p.Gly306ValfsTer25 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.46G>T p.Asp16Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.830A>G p.Lys277Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.964C>G p.Leu322Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.235_238del p.Ile79PhefsTer23 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.342_343del p.Gly115ArgfsTer21 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.2028_2029del p.His676GlnfsTer13 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.832-2A>G - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1351_1354del p.Ser451ProfsTer23 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1239del p.Asp413GlufsTer42 frameshift_variant De novo NA - 32341456 Nakashima M et al. (2020)
c.2156A>G p.His719Arg missense_variant De novo NA Simplex 25969726 Codina-Sol M , et al. (2015)
c.50T>G p.Val17Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.398C>G p.Ser133Ter stop_gained De novo NA Simplex 31696658 da Silva Montenegro EM , et al. (2019)
c.392_395del p.Gly131AspfsTer28 frameshift_variant Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.171_179delinsCGAAG p.Met58GlufsTer20 frameshift_variant De novo NA Simplex 28191889 Stessman HA , et al. (2017)
c.531C>A p.Val177= synonymous_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.2004del p.Leu669TyrfsTer33 frameshift_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.180+8949G>T;c.396+8949G>T;c.378+8949G>T;c.-186+8949G>T;c.345+8949G>T;c.232-11807G>T;c.336+8949G>T; - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
1

High Confidence

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
1

Initial score established: 1

10/1/2021
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

7/1/2021
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

4/1/2021
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

1/1/2021
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

10/1/2020
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

7/1/2020
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

4/1/2020
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

1/1/2020
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

10/1/2019
1

Initial score established: 1

New Scoring Scheme
Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

7/1/2019
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

4/1/2019
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

1/1/2019
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

10/1/2018
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

7/1/2018
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

1/1/2018
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

10/1/2017
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

7/1/2017
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) were reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CUL3 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

4/1/2017
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

1/1/2017
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

10/1/2016
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). A third de novo LoF variant in CUL3 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

7/1/2016
2

Initial score established: 2

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

4/1/2016
2

Initial score established: 2

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2016
2

Initial score established: 2

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2015
1

Initial score established: 1

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2015
2

Initial score established: 2

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

4/1/2015
2

Initial score established: 2

Description

2 de novo LoF mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

1/1/2015
2

Initial score established: 2

Description

2 de novo LGD mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
1

Initial score established: 1

Description

2 de novo LGD mutations (both nonsense variants) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CUL3 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
3

Initial score established: 3

Description

2 de novo LGD mutations (both nonsense variant) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163)

4/1/2014
3

Initial score established: 3

Description

2 de novo LGD mutations (both nonsense variant) reported in the CUL3 gene in unrelated ASD cases (PMIDs 22495309 and 22914163)

Krishnan Probability Score

Score 0.49653465388827

Ranking 2576/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.97406340543885

Ranking 2274/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.901

Ranking 138/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.0052620906397329

Ranking 25/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 30

Ranking 72/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.19041145895806

Ranking 4418/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
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