KCTD1

protein-coding

potassium channel tetramerization domain containing 1, the group of MicroRNA protein coding host genes|KCTD family

Gene summary

This gene encodes a protein containing a BTB (Broad-complex, tramtrack and bric a brac), also known as a POZ (POxvirus and zinc finger) protein-protein interaction domain. The encoded protein negatively regulates the AP-2 family of transcription factors and the Wnt signaling pathway. A mechanism for the modulation of Wnt signaling has been proposed in which the encoded protein enhances ubiquitination and degradation of the beta-catenin protein. Mutations in this gene have been identified in Scalp-ear-nipple (SEN) syndrome. [provided by RefSeq, May 2017]

Previous symbols:

C18orf5

MANE transcript

NM_001142730.3

Inheritance

ClinVar variants

P:13U:146B:37

Top phenotype

scalp-ear-nipple syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr18:26,454,910-26,657,401

External References & Databases

Ensembl (ENSG00000134504)

Transcript & Mutation Effects

hg38 • Region Span ~202.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

scalp-ear-nipple syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008404

Submitter: Labcorp Genetics (formerly Invitae)

scalp-ear-nipple syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008404

Submitter: Orphanet

scalp-ear-nipple syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008404

Submitter: ClinGen

The *KCTD1* (potassium channel tetramerization domain containing 1) gene is located on chromosome 18 at 18q11.2 and encodes a protein containing a BTB (Broad-complex, tramtrack and bric a brac) protein-protein interaction domain. This protein negatively regulates the AP-2 family of transcription factors and the Wnt signaling pathway. Variants in this gene are associated with Scalp-Ear-Nipple (SEN) syndrome, a rare genetic disorder characterized by defects in the scalp, malformed ears, and absent/hypoplastic nipples. *KCTD1* was first reported in connection with SEN syndrome in 2013 (Marneros et al., 2013, PMID: 23541344). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Thirteen variants (12 missense, 1 inframe insertion) reported in 13 probands across five publications have been included in this curation (PMIDs: 8042668; 23541344; 39424163; 33883917; 34456244). The mechanism of pathogenicity is loss-of-function. This gene-disease relationship is also supported by experimental evidence including biochemical function, protein interaction, and model organism data). GST pull-down assays demonstrated *KCTD1* and transcription factor AP-2α interact directly in vitro (PMID: 191153150). Variants in TFAP2A cause Branchio-Oculo-Facial syndrome, which presents with clinical characteristics that overlap with those found in individuals with *KCTD1* variants. *KCTD1* and AP-2α overexpression is shown to decrease β-catenin expression levels (PMID:33000225). The canonical Wnt/β-catenin pathway is one of the downstream regulated pathways of *KCTD1*, and it serves a crucial role in ectoderm patterning and craniofacial development. KCDT1 WT is also required for cell cell viability of keratinocytes (PMID: 38113115). Inactivation of Kctd1 in the kidney (Six2Cre+Kctd1fl/fl mice) results in a terminal differentiation defect in the distal convoluted tubule (DCT) that impairs renal function and leads to a severe interstitial renal fibrosis in the adult with aging, similarly as seen in SEN syndrome patients (PMID: 38113115). In summary, there is definitive evidence supporting the relationship between *KCTD1* and autosomal dominant SEN syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date June 4, 2025 (SOP Version 11).

scalp-ear-nipple syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008404

Submitter: G2P

scalp-ear-nipple syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008404

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCTD1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 131

not providedTotal: 58

Scalp-ear-nipple syndromeTotal: 42

KCTD1-related disorderTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001142730.3. 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			1 clinvar	26 clinvar	1 clinvar	28
missense	9 clinvar	4 clinvar	142 clinvar	9 clinvar	1 clinvar	165
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	9	4	146	35	2	196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001142730.3	RefSeq	NP_001136202.1	5	MANE Select
ENST00000580059.7	Ensembl	ENSP00000463041.2	5	MANE Select
NM_001136205.2	RefSeq	NP_001129677.1	4	Standard
NM_001258221.2	RefSeq	NP_001245150.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Negative regulation of activity of TFAP2 (AP-2) family transcription factors
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors

Biological Process

negative regulation of transcription by RNA polymerase II
negative regulation of transcription, DNA-templated
protein homooligomerization

Molecular Function

transcription corepressor activity
protein binding
transcription factor binding
identical protein binding

Cellular Component

nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000408011
Coding exons: 4
Length: 202492
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125732
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.82	95	160	0.594	0.00000988	1671
Missense (PolyPhen)		15	45.413	0.3303		560
Synonymous	1.19	54	66.3	0.815	0.00000459	513
Loss of Function	2.75	1	10.7	0.0933	5.17e-7	131

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May repress the transcriptional activity of AP-2 family members, including TFAP2A, TFAP2B and TFAP2C to various extent. {ECO:0000269|PubMed:18358072, ECO:0000269|PubMed:19115315}.;
Disease: DISEASE: Scalp-ear-nipple syndrome (SENS) [MIM:181270]: A disease characterized by aplasia cutis congenita of the scalp, breast anomalies that range from hypothelia or athelia to amastia, and minor anomalies of the external ears. Less frequent clinical characteristics include nail dystrophy, dental anomalies, cutaneous syndactyly of the digits, and renal malformations. Penetrance appears to be high, although there is substantial variable expressivity within families. {ECO:0000269|PubMed:23541344}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.0836
RVIS EVS: -0.41
RVIS percentile EVS: 26.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.148

Gene Damage Prediction

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