Human Gene Module / Chromosome 16 / CTCF

CTCFCCCTC-binding factor

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 17
Rare Variants / Common Variants
68 / 0
Aliases
CTCF, MRD21
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
16q22.1
Associated Disorders
DD/NDD, ASD, ID
Relevance to Autism

CTCF interacts with CHD8 (Ishihara et al., 2006); de novo loss-of-function variants in the CHD8 gene have been strongly implicated in ASD. In 2013, de novo variants in the CTCF gene were identified in three individuals with intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (Gregor et al. 2013).

Molecular Function

This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression.

Reports related to CTCF (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Ishihara K , et al. (2006) No -
2 Recent Recommendation Identification of CTCF as a master regulator of the clustered protocadherin genes. Golan-Mashiach M , et al. (2012) No -
3 Recent Recommendation De novo mutations in the genome organizer CTCF cause intellectual disability. Gregor A , et al. (2013) No DD
4 Recent Recommendation Role of CTCF protein in regulating FMR1 locus transcription. Lanni S , et al. (2013) No -
5 Recent Recommendation Dual effect of CTCF loss on neuroprogenitor differentiation and survival. Watson LA , et al. (2014) No -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
8 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
9 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
10 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
11 Support Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report. Bastaki F , et al. (2017) No -
12 Support CTCF deletion syndrome: clinical features and epigenetic delineation. Hori I , et al. (2017) No Autistic features, dysmorphic features
13 Support Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder. Chen F , et al. (2019) No -
14 Recent Recommendation CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum. Konrad EDH , et al. (2019) Yes Feeding difficulties, vision anomalies, microcepha
15 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism. Cappi C , et al. (2019) No -
16 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism. Breuss MW , et al. (2019) Yes -
17 Recent Recommendation Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
Rare Variants   (68)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 23746550 Gregor A , et al. (2013)
- - copy_number_loss De novo NA Simplex 28848059 Hori I , et al. (2017)
- - copy_number_loss De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.638G>A p.Arg213His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1244G>A p.Arg415Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1807C>T p.Arg603Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.-32-5538dup - frameshift_variant De novo NA - 23746550 Gregor A , et al. (2013)
c.853G>T p.Glu285Ter stop_gained De novo NA - 31873310 Breuss MW , et al. (2019)
c.792G>C p.Lys264Asn missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1024C>T p.Arg342Cys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1094A>G p.Lys365Arg missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1102C>T p.Arg368Cys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1118A>T p.His373Leu missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1129C>T p.Arg377Cys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.*956T>A - 3_prime_UTR_variant De novo NA Simplex 27525107 Yuen RK et al. (2016)
c.-32-5225del - frameshift_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.715C>T p.Arg239Trp missense_variant De novo NA - 23746550 Gregor A , et al. (2013)
c.-32-5584dup - frameshift_variant De novo NA Simplex 30893510 Chen F , et al. (2019)
c.782-2A>G - splice_site_variant Unknown - Simplex 31239556 Konrad EDH , et al. (2019)
c.-32-5140_-32-5137del - frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.-32-5381_-32-5375del - frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1016G>A p.Arg339Gln missense_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.1024C>T p.Arg342Cys missense_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.1103G>A p.Arg368His missense_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.1168G>A p.Asp390Asn missense_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.55del p.His19ThrfsTer15 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.848G>A p.Arg283His missense_variant De novo NA Simplex 33004838 Wang T et al. (2020)
c.-32-5299del - frameshift_variant De novo NA Simplex 28619046 Bastaki F , et al. (2017)
c.1016G>A p.Arg339Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1004del p.Gly335GlufsTer27 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.-32-5765dup - frameshift_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.373+2201del - frameshift_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.2000-1G>A - splice_site_variant Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.1699C>T p.Arg567Trp missense_variant De novo NA Simplex 30893510 Chen F , et al. (2019)
c.1430A>C p.His477Pro missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.1244G>A p.Arg415Gln missense_variant De novo NA Simplex 31771860 Cappi C , et al. (2019)
c.-32-4772_-32-4771del - frameshift_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.202dup p.Arg68LysfsTer13 frameshift_variant De novo NA - 23746550 Gregor A , et al. (2013)
c.260G>A p.Arg87Gln missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.1118A>C p.His373Pro missense_variant Unknown - Simplex 31239556 Konrad EDH , et al. (2019)
c.1585G>A p.Asp529Asn missense_variant Unknown - Simplex 31239556 Konrad EDH , et al. (2019)
c.1078A>C p.Ser360Arg missense_variant Unknown - Unknown 31239556 Konrad EDH , et al. (2019)
c.778_781del p.Lys260ValfsTer2 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.833G>T p.Arg278Leu missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.848G>A p.Arg283His missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.979T>A p.Cys327Ser missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.-32-5298_-32-5295del - frameshift_variant De novo NA Simplex 30893510 Chen F , et al. (2019)
c.1006G>C p.Glu336Gln missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1024C>T p.Arg342Cys missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1102C>T p.Arg368Cys missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1117C>G p.His373Asp missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1130G>A p.Arg377His missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1343G>A p.Arg448Gln missense_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1226G>A p.Cys409Tyr missense_variant De novo NA Unknown 31239556 Konrad EDH , et al. (2019)
c.1960C>T p.Arg654Ter stop_gained Familial Maternal Simplex 31239556 Konrad EDH , et al. (2019)
c.1130G>A p.Arg377His missense_variant De novo NA Multiplex 31239556 Konrad EDH , et al. (2019)
c.1133C>T p.Pro378Leu missense_variant De novo NA Multiplex 31239556 Konrad EDH , et al. (2019)
c.1343G>A p.Arg448Gln missense_variant De novo NA Multiplex 31239556 Konrad EDH , et al. (2019)
c.782-1G>T - splice_site_variant Unknown Not maternal Simplex 31239556 Konrad EDH , et al. (2019)
c.71dup p.Cys25ValfsTer56 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.615_618del p.Lys206ProfsTer15 frameshift_variant De novo NA - 31239556 Konrad EDH , et al. (2019)
c.615_618del p.Lys206ProfsTer15 frameshift_variant Unknown - Simplex 31239556 Konrad EDH , et al. (2019)
c.773_776del p.Lys258ArgfsTer4 frameshift_variant De novo NA Simplex 31239556 Konrad EDH , et al. (2019)
c.1699C>T p.Arg567Trp missense_variant De novo NA Multi-generational 31239556 Konrad EDH , et al. (2019)
c.1025G>A p.Arg342His missense_variant Familial Paternal Multi-generational 31239556 Konrad EDH , et al. (2019)
c.118C>T p.Arg40Cys missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.881A>C p.His294Pro missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1133C>T p.Pro378Leu missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features.

Score Delta: Score remained at 3S

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.

10/1/2020
3S
icon
3S

Score remained at 3S

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features.

1/1/2020
3S
icon
3S

Score remained at 3S

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features.

10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3S

Decreased from 3 to 3S

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368). Konrad et al., 2019 found that 39 individuals with CTCF variants presented with a variable neurodevelopmental disorder frequently characterized by feeding difficulties/failure to thrive, developmental delay/intellectual disability, and behavioral abnormalities, including autism and autistic features.

4/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

7/1/2018
4.5 + acc2
icon
3

Decreased from 4.5 + acc2 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

4/1/2018
3
icon
4.5 + acc2

Increased from 3 to 4.5 + acc2

Description

3

10/1/2017
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

7/1/2017
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

4/1/2017
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

7/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

4/1/2015
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

1/1/2015
3
icon
3

Increased from 3 to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

10/1/2014
icon
3

Increased from to 3

Description

A de novo loss-of-function variant in the CTCF gene was identified in an ASD proband from the Simons Simplex Collection (PMID 25363768). De novo variants in this gene (two frameshift, one missense) were previously identified in individuals presenting with developmental delay/intellectual disability, microcephaly, and growth retardation; autistic features were also observed in one of these individuals (PMID 23746550). CTCF interacts with the high confidence ASD gene CHD8 (PMID 16949368).

Krishnan Probability Score

Score 0.59302606652379

Ranking 461/25841 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 0.99792495785254

Ranking 1265/18225 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
Sanders TADA Score

Score 0.15479957022551

Ranking 88/18665 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 4.5

Ranking 298/461 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 0.33017816482418

Ranking 2291/20870 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
CENPE centromere protein E, 312kDa Human Protein Binding 1062 Q02224
DGCR8 DiGeorge syndrome critical region gene 8 Human Protein Binding 54487 Q8WYQ5
HIST1H1E histone cluster 1, H1e Human Protein Binding 3008 P10412
KIAA0020 KIAA0020 Human Protein Binding 9933 Q15397
LMNA lamin A/C Human Protein Binding 4000 P02545
TAF3 TAF3 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 140kDa Human Protein Binding 83860 Q5VWG9
ZBTB33 zinc finger and BTB domain containing 33 Human Protein Binding 10009 Q86T24
ZBTB48 zinc finger and BTB domain containing 48 Human Protein Binding 3104 P10074
ZCRB1 zinc finger CCHC-type and RNA binding motif 1 Human Protein Binding 85437 Q8TBF4
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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