ZBTB18

Summary

ZBTB18 (zinc finger and BTB domain containing 18, HGNC:13030) is a protein-coding gene on chromosome 1q44, encoding Zinc finger and BTB domain-containing protein 18 (Q99592). Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10472 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 375 total — 38 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 42
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_205768

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13030
Approved symbol	ZBTB18
Name	zinc finger and BTB domain containing 18
Location	1q44
Locus type	gene with protein product
Status	Approved
Aliases	C2H2-171, TAZ-1, RP58
Ensembl gene	ENSG00000179456
Ensembl biotype	protein_coding
OMIM	608433
Entrez	10472

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000358704, ENST00000622512, ENST00000696615, ENST00000696616, ENST00000696617, ENST00000696618, ENST00000698634, ENST00000914124

RefSeq mRNA: 4 — MANE Select: NM_205768 NM_001278196, NM_001421566, NM_006352, NM_205768

CCDS: CCDS1622

Canonical transcript exons

ENST00000358704 — 2 exons

Exon	Start	End
ENSE00001916702	244051283	244051444
ENSE00003967869	244053788	244057476

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2540 / max 908.9405, expressed in 1546 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9447	5.8250	1277
9450	3.6476	233
9462	1.7808	441
9446	1.0964	555
9445	0.7659	168
9451	0.6318	112
9460	0.6085	259
9461	0.4779	191
9452	0.2474	53
9449	0.1256	35

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.87	gold quality
paraflocculus	UBERON:0005351	99.69	gold quality
cortical plate	UBERON:0005343	99.63	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.63	gold quality
CA1 field of hippocampus	UBERON:0003881	99.52	gold quality
ganglionic eminence	UBERON:0004023	99.08	gold quality
choroid plexus epithelium	UBERON:0003911	99.06	gold quality
endothelial cell	CL:0000115	99.04	gold quality
cerebellum	UBERON:0002037	98.99	gold quality
orbitofrontal cortex	UBERON:0004167	98.98	gold quality
entorhinal cortex	UBERON:0002728	98.92	gold quality
cerebellar cortex	UBERON:0002129	98.89	gold quality
cerebellar hemisphere	UBERON:0002245	98.87	gold quality
postcentral gyrus	UBERON:0002581	98.51	gold quality
middle temporal gyrus	UBERON:0002771	98.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.43	gold quality
parietal lobe	UBERON:0001872	98.40	gold quality
superior frontal gyrus	UBERON:0002661	98.40	gold quality
pons	UBERON:0000988	98.33	gold quality
biceps brachii	UBERON:0001507	98.33	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.32	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.31	gold quality
vastus lateralis	UBERON:0001379	98.17	gold quality
adult organism	UBERON:0007023	98.00	gold quality
quadriceps femoris	UBERON:0001377	97.99	gold quality
occipital lobe	UBERON:0002021	97.66	gold quality
ventricular zone	UBERON:0003053	97.60	gold quality
primary visual cortex	UBERON:0002436	97.50	gold quality
frontal pole	UBERON:0002795	97.41	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	59.22
E-GEOD-93593	yes	8.32
E-ANND-3	no	4.75

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ID1	Unknown
ID2	Unknown
ID3	Unknown
ID4	Unknown
MAP2	Activation
NEUROG2	Repression
RELN	Unknown
ROBO1	Unknown
SLIT3	Unknown

JASPAR motifs

Motif	Name	Family
MA0698.1	ZBTB18	More than 3 adjacent zinc fingers
MA0698.2	ZBTB18	More than 3 adjacent zinc fingers

JASPAR matrix evidence (PMIDs): PMID:9756912

Upstream regulators (CollecTRI, top): NEUROG2

miRNA regulators (miRDB)

248 targeting ZBTB18, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• Findings indicate that ZNF238 is a novel brain tumor suppressor and its reactivation in tumors could open a novel anticancer strategy. (PMID:20103640)
• RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner. (PMID:22095278)
• repression of the CR2/CD21 promoter can occur through one of the E-box motifs via recruitment of RP58. (PMID:25817480)
• De novo missense and truncating variants in ZBTB18 cause intellectual disability. (PMID:27598823)
• results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans (PMID:28283832)
• This report indicates that haploinsufficiency of additional genes beside ZBTB18 causes the high frequency of corpus callosum anomalies in patients with microdeletions of 1q43q44 and underlines the importance of an NGS-based molecular diagnostic in complex phenotypes (PMID:28345786)
• This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass (PMID:28512252)
• our results suggest that altered transcriptional regulation could represent an important pathological mechanism for ZBTB18 missense variants in brain developmental disease. (PMID:31112317)
• General population ZBTB18 missense variants influence DNA binding and transcriptional regulation. (PMID:32598555)
• CtBP2 interacts with ZBTB18 to promote malignancy of glioblastoma. (PMID:32971103)
• Up-regulated miR-155 is associated with poor prognosis in childhood acute lymphoblastic leukemia and promotes cell proliferation targeting ZNF238. (PMID:33357126)
• The Zinc Finger Protein Zbtb18 Represses Expression of Class I Phosphatidylinositol 3-Kinase Subunits and Inhibits Plasma Cell Differentiation. (PMID:33608456)
• Structure-Based Approaches to Classify the Functional Impact of ZBTB18 Missense Variants in Health and Disease. (PMID:33621064)
• Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis. (PMID:33892786)
• Understanding the impact of ZBTB18 missense variation on transcription factor function in neurodevelopment and disease. (PMID:35083747)
• ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma. (PMID:36414381)
• A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability. (PMID:37525067)
• Expanding the Clinical and Molecular Spectrum of FOXG1- and ZBTB18-Associated Neurodevelopmental Disorders. (PMID:38056433)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zbtb18	ENSDARG00000028228
mus_musculus	Zbtb18	ENSMUSG00000063659
rattus_norvegicus	Zbtb18	ENSRNOG00000004423

Paralogs (36): ZBTB32 (ENSG00000011590), SNAI2 (ENSG00000019549), PRDM1 (ENSG00000057657), PRDM6 (ENSG00000061455), ZNF76 (ENSG00000065029), PATZ1 (ENSG00000100105), MAZ (ENSG00000103495), ZBTB16 (ENSG00000109906), ZNF451 (ENSG00000112200), ZBTB45 (ENSG00000119574), ZNF410 (ENSG00000119725), SNAI1 (ENSG00000124216), ZNF384 (ENSG00000126746), ZBTB1 (ENSG00000126804), VEZF1 (ENSG00000136451), PRDM14 (ENSG00000147596), ZNF276 (ENSG00000158805), ZNF362 (ENSG00000160094), ZNF653 (ENSG00000161914), ZNF281 (ENSG00000162702), ZNF148 (ENSG00000163848), ZNF143 (ENSG00000166478), HIC2 (ENSG00000169635), PRDM10 (ENSG00000170325), ZNF296 (ENSG00000170684), ZNF692 (ENSG00000171163), ZNF575 (ENSG00000176472), HIC1 (ENSG00000177374), ZBTB42 (ENSG00000179627), ZBTB20 (ENSG00000181722), ZBTB7C (ENSG00000184828), SNAI3 (ENSG00000185669), ZFP91 (ENSG00000186660), MTF1 (ENSG00000188786), SCRT2 (ENSG00000215397), SCRT1 (ENSG00000261678)

Protein

Protein identifiers

Zinc finger and BTB domain-containing protein 18 — Q99592 (reviewed: Q99592)

Alternative names: 58 kDa repressor protein, Transcriptional repressor RP58, Translin-associated zinc finger protein 1, Zinc finger protein 238, Zinc finger protein C2H2-171

All UniProt accessions (4): Q99592, A0A8Q3WLD9, A0A8Q3WLX6, A0A8V8TM03

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. Plays a key role in myogenesis by directly repressing the expression of ID2 and ID3, 2 inhibitors of skeletal myogenesis. Also involved in controlling cell division of progenitor cells and regulating the survival of postmitotic cortical neurons. Specifically binds the consensus DNA sequence 5’-[AC]ACATCTG[GT][AC]-3’ which contains the E box core, and acts by recruiting chromatin remodeling multiprotein complexes. May also play a role in the organization of chromosomes in the nucleus.

Subunit / interactions. Interacts with DNMT3A.

Subcellular location. Nucleus.

Tissue specificity. Lymphoid tissues, testis, heart, brain, skeletal muscle, and pancreas and, at much lower level, other tissues.

Disease relevance. Intellectual developmental disorder, autosomal dominant 22 (MRD22) [MIM:612337] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD22 patients have limited or no speech, and variable but characteristic facial features, including round face, prominent forehead, flat nasal bridge, hypertelorism, epicanthal folds, and low-set ears. Other features may include hypotonia, poor growth, microcephaly, agenesis of the corpus callosum, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the krueppel C2H2-type zinc-finger protein family. ZBTB18 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99592-1	1	yes
Q99592-2	2

RefSeq proteins (4): NP_001265125, NP_001408495, NP_006343, NP_991331* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR036236	Znf_C2H2_sf	Homologous_superfamily

Pfam: PF00096, PF00651, PF13894

UniProt features (19 total): zinc finger region 4, modified residue 3, region of interest 3, sequence variant 2, sequence conflict 2, chain 1, domain 1, cross-link 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8P2P	X-RAY DIFFRACTION	4.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99592-F1	52.41	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 157, 516, 517, 273

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 534 (showing top): FREAC2_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GGTGTGT_MIR329, MYOGENIN_Q6, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, CHUNG_BLISTER_CYTOTOXICITY_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, AP4_Q6, MEF2_02, TAL1ALPHAE47_01, FOXO4_01, LHX3_01, FOXO1_01

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), skeletal muscle tissue development (GO:0007519), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	2
chromatin	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
negative regulation of DNA-templated transcription	1
striated muscle tissue development	1
skeletal muscle organ development	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
transition metal ion binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZBTB18	TSN	Q15631	834
ZBTB18	DNMT3A	Q9Y6K1	725
ZBTB18	ID2	Q02363	724
ZBTB18	ID3	Q02535	681
ZBTB18	COX20	Q5RI15	540
ZBTB18	MYOD1	P15172	529
ZBTB18	SPMIP3	Q5SVJ3	468
ZBTB18	CEP170	Q5SW79	452
ZBTB18	CTBP2	P56545	450
ZBTB18	HNRNPU	Q00839	447
ZBTB18	AKT3	Q9Y243	447
ZBTB18	CTBP1	Q13363	442
ZBTB18	FOXJ3	Q9UPW0	430
ZBTB18	KIF26B	Q2KJY2	419
ZBTB18	SLC1A5	Q15758	416

IntAct

38 interactions, top by confidence:

A	B	Type	Score
ZBTB18	CTBP2	psi-mi:“MI:0915”(physical association)	0.790
ZBTB18	CTBP2	psi-mi:“MI:0914”(association)	0.790
CTBP1	ZBTB18	psi-mi:“MI:0915”(physical association)	0.740
ZBTB18	CTBP1	psi-mi:“MI:0915”(physical association)	0.740
FBXL17	BACH1	psi-mi:“MI:0914”(association)	0.730
ZBTB18	CTBP2	psi-mi:“MI:0915”(physical association)	0.720
CTBP2	ZBTB18	psi-mi:“MI:0915”(physical association)	0.720
CTBP1	CBX4	psi-mi:“MI:0914”(association)	0.700
CTBP1	ZBTB18	psi-mi:“MI:0915”(physical association)	0.680
ZBTB18	CTBP1	psi-mi:“MI:0915”(physical association)	0.680
ZBTB18	HSPA8	psi-mi:“MI:0914”(association)	0.640
ZBTB2	ZBTB18	psi-mi:“MI:0915”(physical association)	0.560
MYLIP	ZBTB18	psi-mi:“MI:0915”(physical association)	0.560
PIK3R3	ZBTB18	psi-mi:“MI:0915”(physical association)	0.560
	ZBTB18	psi-mi:“MI:0915”(physical association)	0.400
POMGNT1	ZBTB18	psi-mi:“MI:0915”(physical association)	0.370
ZBTB18	DNASE1L1	psi-mi:“MI:0914”(association)	0.350
CUL4A	DDX39A	psi-mi:“MI:0914”(association)	0.350
ZBTB18	CBR3	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
FBXL17	ENC1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ZBTB18	ZBTB42	psi-mi:“MI:0914”(association)	0.350
ZBTB2	ZBTB18	psi-mi:“MI:0915”(physical association)	0.000
CTBP2	ZBTB18	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (82): ZBTB18 (Two-hybrid), DNMT3A (Reconstituted Complex), ZBTB42 (Affinity Capture-MS), ATXN1L (Affinity Capture-MS), CIC (Affinity Capture-MS), ZNF131 (Affinity Capture-MS), CYP4F12 (Affinity Capture-MS), ZBTB3 (Affinity Capture-MS), ZBTB18 (Affinity Capture-MS), RCBTB2 (Affinity Capture-MS), ZBTB18 (Affinity Capture-RNA), DNMT3A (Reconstituted Complex), ZBTB18 (Reconstituted Complex), DNMT3A (Affinity Capture-Western), ZBTB18 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5NS60, A0JN76, A1YFX5, A2T7G6, A6NJL1, D2HQI1, F1MJR8, O14901, P0CG00, P10754, P22227, P98182, Q0IJ29, Q1L8W0, Q3SWU4, Q5DW34, Q5EAC5, Q5EXX3, Q5RHB5, Q5SXI5, Q5T619, Q66H04, Q6NRM8, Q6NV66, Q6ZSB9, Q7M6U3, Q7TS63, Q7TSH3, Q7ZWZ4, Q801P1, Q86VK4, Q8BKX7, Q8BXX2, Q8NAM6, Q8NAP3, Q8NCP5, Q8R0A2, Q91VW9, Q96IT1, Q96N77

Diamond homologs: A0JN76, A1L2U9, A1YEX3, A1YPR0, A2AAX3, B1WAZ8, B1WBS3, B1WBU4, B2RXF5, D3ZA50, O14867, O15062, O15156, O15209, O43167, O43298, O43829, O88282, O88939, O93567, O95365, P24278, P41182, P41183, P52739, P97302, P97303, Q08376, Q0IH98, Q0IJ29, Q0P4X6, Q0VCJ6, Q13105, Q14526, Q1H9T6, Q1L8W0, Q2T9Z7, Q3B725, Q3B7N9, Q3SWU4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

375 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	34
Uncertain significance	158
Likely benign	97
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1319911	NM_205768.3(ZBTB18):c.550del (p.Asp184fs)	Pathogenic
1328182	NM_205768.3(ZBTB18):c.1456C>T (p.Gln486Ter)	Pathogenic
1333608	NM_205768.3(ZBTB18):c.579G>A (p.Trp193Ter)	Pathogenic
1700158	NM_205768.3(ZBTB18):c.877_881del (p.Asp293fs)	Pathogenic
1801353	NM_205768.3(ZBTB18):c.1142_1146delinsAACCCT (p.Cys381_Pro382delinsTer)	Pathogenic
1802618	NM_205768.3(ZBTB18):c.691_692del (p.Leu231fs)	Pathogenic
208690	NM_205768.3(ZBTB18):c.1382A>G (p.Asn461Ser)	Pathogenic
225892	NM_205768.3(ZBTB18):c.1183C>T (p.Gln395Ter)	Pathogenic
225922	NM_205768.3(ZBTB18):c.943_944del (p.Arg315fs)	Pathogenic
225923	NM_205768.3(ZBTB18):c.133C>T (p.Arg45Ter)	Pathogenic
2579278	GRCh38/hg38 1q44(chr1:244051186-244055631)x1	Pathogenic
2744125	NM_205768.3(ZBTB18):c.1012del (p.Glu338fs)	Pathogenic
3254938	NM_205768.3(ZBTB18):c.562G>T (p.Glu188Ter)	Pathogenic
3648375	NM_205768.3(ZBTB18):c.400del (p.Ala134fs)	Pathogenic
3723313	NM_205768.3(ZBTB18):c.371dup (p.Lys125fs)	Pathogenic
3818262	NM_205768.3(ZBTB18):c.857del (p.Glu286fs)	Pathogenic
397517	NM_205768.3(ZBTB18):c.599del (p.Asp199_Ser200insTer)	Pathogenic
4070586	NM_205768.3(ZBTB18):c.44A>G (p.His15Arg)	Pathogenic
417741	NM_205768.3(ZBTB18):c.583C>T (p.Arg195Ter)	Pathogenic
424193	NM_205768.3(ZBTB18):c.800dup (p.Tyr267Ter)	Pathogenic
431091	NM_205768.3(ZBTB18):c.142C>T (p.Arg48Ter)	Pathogenic
440857	NM_205768.3(ZBTB18):c.1390C>T (p.Arg464Cys)	Pathogenic
4531409	NM_205768.3(ZBTB18):c.1354T>C (p.Cys452Arg)	Pathogenic
4538212	NM_205768.3(ZBTB18):c.942_943dup (p.Arg315fs)	Pathogenic
4634985	NM_205768.3(ZBTB18):c.162C>A (p.Cys54Ter)	Pathogenic
4712535	NM_205768.3(ZBTB18):c.1282_1283del (p.Phe428fs)	Pathogenic
4765590	NM_205768.3(ZBTB18):c.1019_1020dup (p.Ala341fs)	Pathogenic
4813789	NM_205768.3(ZBTB18):c.1322_1325del (p.His441fs)	Pathogenic
4819202	Single allele	Pathogenic
504179	NM_205768.3(ZBTB18):c.1342dup (p.Thr448fs)	Pathogenic

SpliceAI

433 predictions. Top by Δscore:

Variant	Effect	Δscore
1:244051413:A:T	donor_gain	1.0000
1:244053782:CCCCA:C	acceptor_loss	1.0000
1:244053783:CCCA:C	acceptor_loss	1.0000
1:244053784:CCA:C	acceptor_loss	1.0000
1:244053785:CA:C	acceptor_loss	1.0000
1:244053787:G:GC	acceptor_loss	1.0000
1:244053092:T:A	acceptor_gain	0.9900
1:244053786:A:AG	acceptor_gain	0.9900
1:244053787:G:GG	acceptor_gain	0.9900
1:244053787:GGTT:G	acceptor_gain	0.9800
1:244051412:G:GT	donor_gain	0.9700
1:244051417:GACT:G	donor_gain	0.9700
1:244053786:AG:A	acceptor_gain	0.9700
1:244053787:GG:G	acceptor_gain	0.9700
1:244051428:GTT:G	donor_gain	0.9500
1:244051429:TTT:T	donor_gain	0.9500
1:244053787:GGT:G	acceptor_gain	0.9500
1:244051430:TTA:T	donor_gain	0.9200
1:244051431:TAT:T	donor_gain	0.9200
1:244051432:A:G	donor_gain	0.9200
1:244051441:AAAG:A	donor_loss	0.8800
1:244051442:AAG:A	donor_loss	0.8800
1:244051443:AG:A	donor_loss	0.8800
1:244051444:GGTA:G	donor_loss	0.8800
1:244051445:G:T	donor_loss	0.8800
1:244051446:T:G	donor_loss	0.8800
1:244053067:A:AG	acceptor_gain	0.8600
1:244053068:G:GG	acceptor_gain	0.8600
1:244053068:GTAAA:G	acceptor_gain	0.8300
1:244053069:T:G	acceptor_gain	0.8100

AlphaMissense

3548 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:244054915:T:C	C372R	1.000
1:244055056:T:C	F419L	1.000
1:244055058:C:A	F419L	1.000
1:244055058:C:G	F419L	1.000
1:244055119:T:C	C440R	1.000
1:244055140:T:C	F447L	1.000
1:244055141:T:C	F447S	1.000
1:244055142:C:A	F447L	1.000
1:244055142:C:G	F447L	1.000
1:244055224:T:C	F475L	1.000
1:244055225:T:C	F475S	1.000
1:244055226:C:A	F475L	1.000
1:244055226:C:G	F475L	1.000
1:244054103:C:A	A101D	0.999
1:244054917:C:G	C372W	0.999
1:244054936:T:C	F379L	0.999
1:244054937:T:C	F379S	0.999
1:244054938:C:A	F379L	0.999
1:244054938:C:G	F379L	0.999
1:244054955:T:C	L385P	0.999
1:244054967:T:C	L389P	0.999
1:244055035:T:C	C412R	0.999
1:244055037:C:G	C412W	0.999
1:244055044:T:A	C415S	0.999
1:244055044:T:C	C415R	0.999
1:244055045:G:C	C415S	0.999
1:244055046:T:G	C415W	0.999
1:244055057:T:C	F419S	0.999
1:244055057:T:G	F419C	0.999
1:244055075:T:C	L425P	0.999

dbSNP variants (sampled 300 via entrez): RS1000013138 (1:244048025 G>A), RS1000056799 (1:244054888 C>G), RS1000522620 (1:244051958 A>G), RS1000553627 (1:244052238 C>G,T), RS1000659553 (1:244056432 A>C), RS1000764888 (1:244048258 T>C), RS1000946649 (1:244056690 A>C,T), RS1001206573 (1:244047754 CCT>C), RS1001311134 (1:244053188 C>T), RS1001558702 (1:244057972 C>T), RS1001903216 (1:244057746 A>G), RS1002344723 (1:244051930 T>G), RS1002661969 (1:244052828 A>C,T), RS1002890999 (1:244056963 G>A), RS1003347713 (1:244050210 C>T)

Disease associations

OMIM: gene MIM:608433 | disease phenotypes: MIM:612337, MIM:212140

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 22	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (3): intellectual disability, autosomal dominant 22 (MONDO:0012869), intellectual disability (MONDO:0001071), systemic primary carnitine deficiency disease (MONDO:0008919)

Orphanet (2): Systemic primary carnitine deficiency (Orphanet:158), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000506	Telecanthus
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001611	Hypernasal speech
HP:0002020	Gastroesophageal reflux
HP:0002121	Generalized non-motor (absence) seizure
HP:0002190	Choroid plexus cyst
HP:0002376	Developmental regression
HP:0002553	Highly arched eyebrow
HP:0003189	Long nose

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001017_13	Diabetic retinopathy	2.000000e-06
GCST001017_8	Diabetic retinopathy	1.000000e-07
GCST001859_8	Thiazide-induced adverse metabolic effects in hypertensive patients	1.000000e-06
GCST002576_5	Epithelial ovarian cancer	4.000000e-06
GCST002927_12	Mercury levels	9.000000e-06
GCST007324_75	Adventurousness	5.000000e-13
GCST007325_63	General risk tolerance (MTAG)	2.000000e-18

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0008579	risk-taking behaviour

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C567346	Chromosome 1q43-Q44 Deletion Syndrome (supp.)
C536778	Systemic carnitine deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases methylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression	1
sulforaphane	increases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Oxaliplatin	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Vehicle Emissions	increases abundance, increases expression	1
Fluorouracil	increases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	increases expression, affects cotreatment	1
Indomethacin	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders