CUX2

protein-coding

cut like homeobox 2, the group of MicroRNA protein coding host genes|CUT class homeoboxes and pseudogenes

Gene summary

This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. A similar gene, whose gene product possesses different DNA-binding activities, is located on chromosome on chromosome 7. Two pseudogenes of this gene have been identified on chromosomes 10 and 4. [provided by RefSeq, Jan 2013]

Previous symbols:

CUTL2

MANE transcript

NM_015267.4

Inheritance

ClinVar variants

P:4U:330B:195

Top phenotype

Developmental and epileptic encephalopathy 67

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr12:111,034,165-111,350,554

External References & Databases

Ensembl (ENSG00000111249)

Transcript & Mutation Effects

hg38 • Region Span ~316.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

genetic developmental and epileptic encephalopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*CUX2* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy (DEE) in 2012 (Rauch et al., PMID: 23020937). The typical clinical presentation includes intellectual disability and seizure onset in the first year of life, sometimes associated with movement disorders, autism, hypotonia, and abnormal brain MRI (PMID: 29630738). Some individuals were reported to have a Rett-like phenotype including stereotypic movements, breathing abnormalities, and sleep disruption (PMID: 29630738). A recurrent de novo missense variant (c.1768G>A, p.Glu590Lys) accounts for the majority of published variants in this gene and has been identified in at least 11 probands in four publications (PMIDs: 29630738, 23020937, 29795476, 30842224). Other missense variants (p.Thr642Met and p.Arg1458Gln) were given zero points due to a lack of detailed clinical information and presence of the variants in gnomAD (PMIDs: 31785789, 35571021). Finally, a de-novo p.Thr945Met missense variant was identified in a patient with a history of three febrile seizures, intellectual disability, and developmental delay. It was not scored at this time due to the proband’s milder phenotypic presentation and uncertainty about the association of variants other than p.Glu590Lys with DEE (PMID: 35846140).The mechanism of pathogenicity is currently unknown and there is no experimental evidence available at this time. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date May 16, 2023 (SOP Version 9).

developmental and epileptic encephalopathy, 67STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0029138

Submitter: G2P

developmental and epileptic encephalopathy, 67STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0029138

Submitter: Labcorp Genetics (formerly Invitae)

Lennox-Gastaut syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016532

Submitter: Orphanet

developmental and epileptic encephalopathy, 67STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0029138

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 67AD

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: 29630738; 29795476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CUX2 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 236

Inborn genetic diseasesTotal: 200

not specifiedTotal: 122

Developmental and epileptic encephalopathy, 67Total: 74

CUX2-related disorderTotal: 73

Intellectual disabilityTotal: 6

Developmental and epileptic encephalopathyTotal: 2

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015267.4. 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			2 clinvar	103 clinvar	2 clinvar	107
missense	1 clinvar	2 clinvar	312 clinvar	86 clinvar	3 clinvar	404
nonsense			5 clinvar			5
start loss						0
frameshift		1 clinvar	7 clinvar			8
splice donor/acceptor (+/-2bp)			4 clinvar	1 clinvar		5
Total	1	3	330	190	5	529

Highest pathogenic variant AF is 6.2467984e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015267.4	RefSeq	NP_056082.2	22	MANE Select
ENST00000261726.11	Ensembl	ENSP00000261726.6	22	MANE Select
NM_001370598.1	RefSeq	NP_001357527.1	20	Standard
ENST00000397643.3	Ensembl	ENSP00000380765.3	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
short-term memory
positive regulation of gene expression
Golgi vesicle transport
positive regulation of dendrite morphogenesis

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
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
sequence-specific DNA binding

Cellular Component

Golgi membrane
nucleus
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261726
Coding exons: 22
Length: 316531
Individuals with no LoFs: 124785
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 124794
p: 0.0000361

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.18	615	881	0.698	0.0000575	9418
Missense (PolyPhen)		161	324.11	0.49675		3372
Synonymous	1.62	365	407	0.898	0.0000292	3110
Loss of Function	6.67	6	63.2	0.0949	0.00000305	753

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00013	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be a transcription factor involved in neural specification. Binds to DNA in a sequence-specific manner (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.280
RVIS EVS: -2.08
RVIS percentile EVS: 1.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.227

Gene Damage Prediction

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