Human Gene Module / Chromosome 12 / CEP290

CEP290Centrosomal protein 290kDa

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
23 / 0
Aliases
CEP290, 3H11Ag,  BBS14,  CT87,  JBTS5,  LCA10,  MKS4,  NPHP6,  POC3,  SLSN6,  rd16
Associated Syndromes
Joubert syndrome
Chromosome Band
12q21.32
Associated Disorders
ID, ASD
Relevance to Autism

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report.

Molecular Function

Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition. Required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells; may play a role in ciliary transport processes. Defects in this gene are associated with several diseases, including Joubert syndrome 5 (JBTS5) [MIM:610188], Senior-Loken syndrome 6 (SLSN6) [MIM:610189], Leber congenital amaurosis 10 (LCA10) [MIM:611755], Meckel syndrome 4 (MKS4) [MIM:611134], and Bardet-Biedl syndrome 14 (BBS14) [MIM:209900].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CEP290 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes Coppieters F , et al. (2010) No ASD, ID
2 Support Familial intellectual disability in an Iranian family with a novel truncating mutation in CEP290 Ghaffari SR , et al. (2013) No -
3 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
5 Recent Recommendation A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology Migliavacca E , et al. (2015) No -
6 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No ID, hypotonia
7 Recent Recommendation A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery Kilander MBC , et al. (2018) Yes -
8 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
9 Support - Mitani T et al. (2021) No -
10 Support - Woodbury-Smith M et al. (2022) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
13 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes ADHD, epilepsy/seizures
14 Support - Tamam Khalaf et al. (2024) No -
15 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2991+1655A>G - stop_gained - - - 20683928 Coppieters F , et al. (2010)
c.322C>T p.Arg108Ter stop_gained - - - 20683928 Coppieters F , et al. (2010)
c.1189+1G>A - splice_site_variant - - - 20683928 Coppieters F , et al. (2010)
c.4393C>T p.Arg1465Ter stop_gained - - - 20683928 Coppieters F , et al. (2010)
c.4723A>T p.Lys1575Ter stop_gained - - - 20683928 Coppieters F , et al. (2010)
c.2991+1655A>G - intron_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.6835T>A p.Leu2279Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.830A>G p.Glu277Gly missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5519_5537del p.Lys1840ArgfsTer5 frameshift_variant - - - 20683928 Coppieters F , et al. (2010)
c.5668G>T p.Gly1890Ter stop_gained Familial Both parents - 38438125 Tamam Khalaf et al. (2024)
c.5668G>T p.Gly1890Ter stop_gained Familial Both parents Simplex 34582790 Mitani T et al. (2021)
c.5668G>T p.Gly1890Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.7048C>T p.Gln2350Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.5668G>T p.Gly1890Ter stop_gained Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
c.1834C>T p.Leu612Phe missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
c.1833del p.Leu612PhefsTer5 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3411dup p.Ile1138AspfsTer8 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5271_5272insT p.Ala1758CysfsTer3 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5666del p.Glu1889GlyfsTer7 frameshift_variant Familial Both parents Multiplex 24175892 Ghaffari SR , et al. (2013)
c.1079G>A p.Arg360Gln missense_variant Familial Maternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2119C>T p.Gln707Ter missense_variant Familial Paternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1991A>G p.Asp664Gly missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.5237G>A p.Arg1746Gln missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report. Inherited heterozygous missense variants in the CEP290 gene were identified in affected individuals from two extended multiplex ASD families in Cukier et al., 2014. Functional characterization of one of these ASD-associated missense variants (p.Arg1746Gln) in transfected NIH/3T3 cells, patient-derived iPSCs, and transfected mouse cerebellar slices in Kilander et al., 2018 demonstrated that this variant resulted in disruption of the molecular integrity of the primary cilium, impaired Shh signaling, and failure to regulate the proliferation of granule cell progenitors.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report. Inherited heterozygous missense variants in the CEP290 gene were identified in affected individuals from two extended multiplex ASD families in Cukier et al., 2014. Functional characterization of one of these ASD-associated missense variants (p.Arg1746Gln) in transfected NIH/3T3 cells, patient-derived iPSCs, and transfected mouse cerebellar slices in Kilander et al., 2018 demonstrated that this variant resulted in disruption of the molecular integrity of the primary cilium, impaired Shh signaling, and failure to regulate the proliferation of granule cell progenitors.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report. Inherited heterozygous missense variants in the CEP290 gene were identified in affected individuals from two extended multiplex ASD families in Cukier et al., 2014. Functional characterization of one of these ASD-associated missense variants (p.Arg1746Gln) in transfected NIH/3T3 cells, patient-derived iPSCs, and transfected mouse cerebellar slices in Kilander et al., 2018 demonstrated that this variant resulted in disruption of the molecular integrity of the primary cilium, impaired Shh signaling, and failure to regulate the proliferation of granule cell progenitors.

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report. Inherited heterozygous missense variants in the CEP290 gene were identified in affected individuals from two extended multiplex ASD families in Cukier et al., 2014. Functional characterization of one of these ASD-associated missense variants (p.Arg1746Gln) in transfected NIH/3T3 cells, patient-derived iPSCs, and transfected mouse cerebellar slices in Kilander et al., 2018 demonstrated that this variant resulted in disruption of the molecular integrity of the primary cilium, impaired Shh signaling, and failure to regulate the proliferation of granule cell progenitors.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
S
icon
4S

Increased from S to 4S

Description

33% of patients with CEP-290 isolated Leber Congenital Amaurosis ascertained by Coppieters et al., 2010, also presented with mental retardation and/or autism, in contrast to only 8% of patients with mutations in other LCA-related genes; most specifically, three patients with CEP290-related LCA and one patient with CEP290-related Senior-Loken syndrome presented with autism in this report. Inherited heterozygous missense variants in the CEP290 gene were identified in affected individuals from two extended multiplex ASD families in Cukier et al., 2014. Functional characterization of one of these ASD-associated missense variants (p.Arg1746Gln) in transfected NIH/3T3 cells, patient-derived iPSCs, and transfected mouse cerebellar slices in Kilander et al., 2018 demonstrated that this variant resulted in disruption of the molecular integrity of the primary cilium, impaired Shh signaling, and failure to regulate the proliferation of granule cell progenitors.

Reports Added
[A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery.2018]
Krishnan Probability Score

Score 0.41487030265197

Ranking 21573/25841 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.
Original Source
ExAC Score

Score 1.0391208111792E-34

Ranking 18182/18225 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
Original Source
Sanders TADA Score

Score 0.95064641748311

Ranking 18574/18665 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).
Original Source
Larsen Cumulative Evidence Score

Score 6

Ranking 253/461 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.
Original Source
Zhang D Score

Score -0.1934799315628

Ranking 15270/20870 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.
Original Source
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