CTCF

protein-coding

CCCTC-binding factor, the group of Zinc fingers C2H2-type|Cilia and flagella associated

Gene summary

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. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

MANE transcript

NM_006565.4

Inheritance

ClinVar variants

P:110U:208B:69

Top phenotype

Intellectual developmental disorder, autosomal dominant 21

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr16:67,562,467-67,639,177

External References & Databases

Ensembl (ENSG00000102974)

Transcript & Mutation Effects

hg38 • Region Span ~76.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

CTCF-related neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014213

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

The CTCF gene encodes a sequence-specific DNA binding protein regulating chromatin organization and RNA transcription. The relationship between CTCF variants and autosomal dominant syndromic intellectual disability was first reported in 2013 (Gregor et al., PMID: 23746550). Since then, more than 40 truncating and missense variants, most of which are de novo, have been reported in the literature (PMIDs: 28619046, 28848059, 30893510, 31239556). Common clinical features in affected individuals include developmental delay and cognitive impairment of variable severity, ranging from normal IQ to severe intellectual disability, feeding difficulties, behavioral abnormalities including autism or autistic features, and minor facial dysmorphism. Less frequent features include growth restriction, microcephaly, vision abnormalities, and cardiac defects. Transcriptome analysis of individuals carrying either truncating or missense variants showed a similar deregulation pattern of downstream genes with roles in neurodevelopmental disorder and biological processes such as transcriptional regulation (PMIDs: 23746550, 31239556). The disease association and loss-of-function mechanism of this gene are further supported by fly and mouse models (PMIDs: 31239556, 22854024, 24553927, 27880914, 29133437, 30377227). In summary, CTCF is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 7/21/2021 (SOP Version 8).

CTCF-related neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014213

Submitter: Ambry Genetics

CTCF-related neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014213

Submitter: Labcorp Genetics (formerly Invitae)

CTCF-related neurodevelopmental disorderSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014213

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 21AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23746550

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CTCF variants in ClinVar

14 Conditions Cataloged

not providedTotal: 215

CTCF-related neurodevelopmental disorderTotal: 106

Inborn genetic diseasesTotal: 91

CTCF-related disorderTotal: 42

not specifiedTotal: 35

Intellectual disabilityTotal: 5

See casesTotal: 3

CTCF-related syndromic intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006565.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	49 clinvar	3 clinvar	55
missense	8 clinvar	44 clinvar	192 clinvar	17 clinvar		261
nonsense	5 clinvar	6 clinvar	2 clinvar			13
start loss		1 clinvar	1 clinvar			2
frameshift	23 clinvar	14 clinvar	5 clinvar			42
splice donor/acceptor (+/-2bp)	3 clinvar	6 clinvar	5 clinvar			14
Total	39	71	208	66	3	387

Highest pathogenic variant AF is 0.0000049906052

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006565.4	RefSeq	NP_006556.1	10	MANE Select
ENST00000264010.10	Ensembl	ENSP00000264010.4	10	MANE Select
NM_001191022.2	RefSeq	NP_001177951.1	8	Standard
NM_001363916.2	RefSeq	NP_001350845.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ctcf	Danio rerio	Structure: post-vent region Quality: curved dorsal abnormal

Gene / Model

Organism

Observed Phenotype

ctcf

Danio rerio

Structure: post-vent region

Quality: curved dorsal

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MECP2 and Associated Rett Syndrome
Prion disease pathway
Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways
ctcf: first multivalent nuclear factor
TGF_beta_Receptor

Biological Process

negative regulation of transcription by RNA polymerase II
DNA methylation
regulation of gene expression by genetic imprinting
chromosome segregation
negative regulation of cell population proliferation

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

chromosome, centromeric region
condensed chromosome
nucleus
nucleoplasm
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264010
Coding exons: 10
Length: 76777
Individuals with no LoFs: 125615
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125617
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.44	174	434	0.401	0.0000255	4861
Missense (PolyPhen)		24	144.2	0.16643		1579
Synonymous	-1.36	171	150	1.14	0.00000900	1312
Loss of Function	5.08	1	32.0	0.0312	0.00000170	404

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000090	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin binding factor that binds to DNA sequence specific sites. Involved in transcriptional regulation by binding to chromatin insulators and preventing interaction between promoter and nearby enhancers and silencers. Acts as transcriptional repressor binding to promoters of vertebrate MYC gene and BAG1 gene. Also binds to the PLK and PIM1 promoters. Acts as a transcriptional activator of APP. Regulates APOA1/C3/A4/A5 gene cluster and controls MHC class II gene expression. Plays an essential role in oocyte and preimplantation embryo development by activating or repressing transcription. Seems to act as tumor suppressor. Plays a critical role in the epigenetic regulation. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, binding within the H19 imprinting control region (ICR) mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to IGF2. Plays a critical role in gene silencing over considerable distances in the genome. Preferentially interacts with unmethylated DNA, preventing spreading of CpG methylation and maintaining methylation-free zones. Inversely, binding to target sites is prevented by CpG methylation. Plays a important role in chromatin remodeling. Can dimerize when it is bound to different DNA sequences, mediating long-range chromatin looping. Mediates interchromosomal association between IGF2/H19 and WSB1/NF1 and may direct distant DNA segments to a common transcription factory. Causes local loss of histone acetylation and gain of histone methylation in the beta-globin locus, without affecting transcription. When bound to chromatin, it provides an anchor point for nucleosomes positioning. Seems to be essential for homologous X-chromosome pairing. May participate with Tsix in establishing a regulatable epigenetic switch for X chromosome inactivation. May play a role in preventing the propagation of stable methylation at the escape genes from X- inactivation. Involved in sister chromatid cohesion. Associates with both centromeres and chromosomal arms during metaphase and required for cohesin localization to CTCF sites. Regulates asynchronous replication of IGF2/H19. Plays a role in the recruitment of CENPE to the pericentromeric/centromeric regions of the chromosome during mitosis (PubMed:26321640). {ECO:0000269|PubMed:11743158, ECO:0000269|PubMed:16815976, ECO:0000269|PubMed:17827499, ECO:0000269|PubMed:18347100, ECO:0000269|PubMed:18413740, ECO:0000269|PubMed:18550811, ECO:0000269|PubMed:18654629, ECO:0000269|PubMed:19322193, ECO:0000269|PubMed:26321640, ECO:0000269|PubMed:8649389, ECO:0000269|PubMed:9591631}.;
Disease: DISEASE: Mental retardation, autosomal dominant 21 (MRD21) [MIM:615502]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD21 features include short stature, microcephaly, and developmental delay. {ECO:0000269|PubMed:23746550}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.251

Intolerance Scores

LoFtool: 0.0330
RVIS EVS: -0.29
RVIS percentile EVS: 32.94

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium