KANSL1

Summary

KANSL1 (KAT8 regulatory NSL complex subunit 1, HGNC:24565) is a protein-coding gene on chromosome 17q21.31, encoding KAT8 regulatory NSL complex subunit 1 (Q7Z3B3). Non-catalytic component of the NSL histone acetyltransferase complex, a multiprotein complex that mediates histone H4 acetylation at ‘Lys-5’- and ‘Lys-8’ (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiation. It is a selective cancer dependency (DepMap: 82.8% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome.

Source: NCBI Gene 284058 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Koolen-de Vries syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 85
• Clinical variants (ClinVar): 1,509 total — 77 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 81
• Cancer dependency (DepMap): dependent in 82.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015443

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24565
Approved symbol	KANSL1
Name	KAT8 regulatory NSL complex subunit 1
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP727C091, MSL1v1, CENP-36, NSL1
Ensembl gene	ENSG00000120071
Ensembl biotype	protein_coding
OMIM	612452
Entrez	284058

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 21 protein_coding, 12 protein_coding_CDS_not_defined, 10 retained_intron

ENST00000262419, ENST00000432791, ENST00000571698, ENST00000572218, ENST00000572904, ENST00000573286, ENST00000573682, ENST00000574590, ENST00000574655, ENST00000574963, ENST00000575318, ENST00000576137, ENST00000576248, ENST00000576739, ENST00000576870, ENST00000577114, ENST00000638269, ENST00000638275, ENST00000638291, ENST00000638551, ENST00000638902, ENST00000639099, ENST00000639150, ENST00000639279, ENST00000639356, ENST00000639375, ENST00000639467, ENST00000639520, ENST00000639531, ENST00000639805, ENST00000639853, ENST00000640092, ENST00000640519, ENST00000640636, ENST00000640751, ENST00000648792, ENST00000902801, ENST00000902802, ENST00000902803, ENST00000902804, ENST00000902805, ENST00000918918, ENST00000918919

RefSeq mRNA: 26 — MANE Select: NM_015443 NM_001193465, NM_001193466, NM_001379198, NM_001405854, NM_001405855, NM_001405856, NM_001405857, NM_001405858, NM_001405859, NM_001405860, NM_001405861, NM_001405872, NM_001405873, NM_001405874, NM_001405875, NM_001405876, NM_001405877, NM_001405878, NM_001405879, NM_001405880, NM_001405881, NM_001405882, NM_001405883, NM_001405884, NM_001405885, NM_015443

CCDS: CCDS11503, CCDS74084, CCDS92348

Canonical transcript exons

ENST00000432791 — 15 exons

Exon	Start	End
ENSE00002344967	46039702	46039884
ENSE00002663617	46192823	46193429
ENSE00003465940	46038538	46038686
ENSE00003519131	46066537	46066732
ENSE00003528610	46033080	46033192
ENSE00003543639	46034161	46034285
ENSE00003563989	46082441	46082542
ENSE00003573153	46067549	46067667
ENSE00003614505	46170855	46172232
ENSE00003651121	46050533	46050704
ENSE00003662350	46094560	46094701
ENSE00003663322	46039027	46039215
ENSE00003666073	46032047	46032299
ENSE00003667509	46033403	46033460
ENSE00003679909	46029916	46031703

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1967 / max 149.4517, expressed in 1803 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166578	3.7492	1475
166573	3.3697	1224
166579	2.7581	1255
166575	1.9114	1005
166574	1.8092	968
166581	1.0800	630
166577	0.5068	293
166576	0.3088	151
166580	0.2980	142
166568	0.2634	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	97.61	gold quality
colonic epithelium	UBERON:0000397	97.11	gold quality
thymus	UBERON:0002370	96.07	gold quality
ganglionic eminence	UBERON:0004023	95.62	gold quality
embryo	UBERON:0000922	95.61	gold quality
calcaneal tendon	UBERON:0003701	95.59	gold quality
sural nerve	UBERON:0015488	95.25	gold quality
ventricular zone	UBERON:0003053	95.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.11	gold quality
lower esophagus mucosa	UBERON:0035834	94.60	gold quality
cortical plate	UBERON:0005343	94.55	gold quality
adrenal tissue	UBERON:0018303	94.33	gold quality
cerebellar cortex	UBERON:0002129	93.87	gold quality
cerebellar hemisphere	UBERON:0002245	93.87	gold quality
pylorus	UBERON:0001166	93.78	gold quality
granulocyte	CL:0000094	93.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.70	gold quality
right uterine tube	UBERON:0001302	93.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.51	gold quality
cerebellum	UBERON:0002037	93.46	gold quality
trabecular bone tissue	UBERON:0002483	93.39	gold quality
skin of leg	UBERON:0001511	93.31	gold quality
skin of abdomen	UBERON:0001416	93.29	gold quality
right lobe of thyroid gland	UBERON:0001119	93.21	gold quality
corpus callosum	UBERON:0002336	93.20	gold quality
ectocervix	UBERON:0012249	92.98	gold quality
body of pancreas	UBERON:0001150	92.81	gold quality
right ovary	UBERON:0002118	92.73	gold quality
left ovary	UBERON:0002119	92.71	gold quality
body of uterus	UBERON:0009853	92.63	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	6.66
E-ANND-3	no	2.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting KANSL1, 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-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4802-3P	99.72	70.13	1273

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 82.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• findings show that de novo loss-of-function mutations in KANSL1 cause a full del(17q21.31) phenotype in 2 unrelated individuals that lack deletion at 17q21.31; findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1 (PMID:22544367)
• essential for mitotic spindle assembly and chromosome segregation (PMID:26243146)
• KANSL1 gene haploinsufficiency is necessary and sufficient to cause the full spectrum of the 17q21.31 microdeletion syndrome. (PMID:26293599)
• In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. (PMID:26424144)
• This case expands the mild end of the neurodevelopmental spectrum seen in children with de novo KANSL1 mutation and KdVS. (PMID:28211987)
• These results show that a KANSL1 microduplication, in combination with the 22q11.2 deletion, is associated with increased risk of CHD in these patients, suggesting that KANSL1 plays a role as a modifier gene in 22q11.2DS patients. (PMID:28496102)
• One variant, p.Lys104Thr, was predicted damaging and appeared overrepresented in our 90-patient cohort compared to Genome Aggregation Database allele frequency (0.217 to 0.116). However, there was no difference in p.Lys104Thr allele frequency in the follow-up childhood epilepsy with centrotemporal spikes (CECTS) and atypical childhood epilepsy with centrotemporal spikes (ACECTS) cohort and controls. (PMID:29352316)
• Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition. (PMID:33229045)
• Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome. (PMID:33361104)
• Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma. (PMID:35575789)
• A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells. (PMID:38282074)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kansl1b	ENSDARG00000088238
danio_rerio	kansl1a	ENSDARG00000090895
mus_musculus	Kansl1	ENSMUSG00000018412
rattus_norvegicus	Kansl1	ENSRNOG00000053680
drosophila_melanogaster	nsl1	FBGN0262527

Paralogs (1): KANSL1L (ENSG00000144445)

Protein

Protein identifiers

KAT8 regulatory NSL complex subunit 1 — Q7Z3B3 (reviewed: Q7Z3B3)

Alternative names: MLL1/MLL complex subunit KANSL1, MSL1 homolog 1, NSL complex protein NSL1, Non-specific lethal 1 homolog

All UniProt accessions (11): Q7Z3B3, A0A0G2JQP8, A0A1W2PPV8, A0A1W2PQT4, A0A1W2PRA9, A0A1W2PRB5, A0A1W2PRR3, A0A1W2PS83, A0A3B3IT55, A0A9S7M8F4, I3L233

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the NSL histone acetyltransferase complex, a multiprotein complex that mediates histone H4 acetylation at ‘Lys-5’- and ‘Lys-8’ (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiation. The NSL complex also acts as a regulator of gene expression in mitochondria. In addition to its role in transcription, KANSL1 also plays an essential role in spindle assembly during mitosis. Associates with microtubule ends and contributes to microtubule stability.

Subunit / interactions. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1. Interacts (via PEHE domain) with KAT8 (via HAT domain); the interaction is direct. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BACC1, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore. Mitochondrion. Cytoplasm. Cytoskeleton. Spindle pole.

Tissue specificity. Expressed in the brain.

Disease relevance. Koolen-De Vries syndrome (KDVS) [MIM:610443] An autosomal dominant, multisystem disorder characterized by hypotonia, developmental delay, moderate to severe intellectual disability, and distinctive dysmorphic features including tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. Expressive language development is particularly impaired compared with receptive language or motor skills. Additional features include social and friendly behavior, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z3B3-1	1	yes
Q7Z3B3-2	2
Q7Z3B3-4	3

RefSeq proteins (26): NP_001180394, NP_001180395, NP_001366127, NP_001392783, NP_001392784, NP_001392785, NP_001392786, NP_001392787, NP_001392788, NP_001392789, NP_001392790, NP_001392801, NP_001392802, NP_001392803, NP_001392804, NP_001392805, NP_001392806, NP_001392807, NP_001392808, NP_001392809, NP_001392810, NP_001392811, NP_001392812, NP_001392813, NP_001392814, NP_056258* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026180	NSL1	Family
IPR029332	PEHE_dom	Domain

Pfam: PF15275

UniProt features (51 total): sequence variant 9, region of interest 8, mutagenesis site 8, compositionally biased region 7, modified residue 7, splice variant 3, sequence conflict 3, cross-link 2, chain 1, domain 1, coiled-coil region 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4CY1	X-RAY DIFFRACTION	1.5
4CY2	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z3B3-F1	51.07	0.05

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 (9): 104, 249, 268, 991, 994, 1003, 1045, 262, 331

Mutagenesis-validated functional residues (8):

Position	Phenotype
852–855	abolishes kat8 histone acetyltransferase activity.
856–859	strongly reduces kat8 histone acetyltransferase activity.
860–863	strongly reduces kat8 histone acetyltransferase activity.
864–867	abolishes kat8 histone acetyltransferase activity.
868–871	reduces kat8 histone acetyltransferase activity.
910	abolishes interaction with kat8.
917	no effect on interaction with kat8.
921	abolishes interaction with kat8.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-9772755	Formation of WDR5-containing histone-modifying complexes
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization
R-HSA-74160	Gene expression (Transcription)
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 585 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, WANG_CLIM2_TARGETS_UP, GOBP_CHROMOSOME_LOCALIZATION, GOZGIT_ESR1_TARGETS_DN, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CTATGCA_MIR153, ACTGCAG_MIR173P, PUJANA_CHEK2_PCC_NETWORK, GOBP_ORGANELLE_FISSION, GROSS_HYPOXIA_VIA_ELK3_UP, GROSS_HYPOXIA_VIA_HIF1A_UP, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN, GOBP_MITOTIC_NUCLEAR_DIVISION

GO Biological Process (3): chromatin organization (GO:0006325), positive regulation of DNA-templated transcription (GO:0045893), regulation of mitochondrial transcription (GO:1903108)

GO Molecular Function (2): histone acetyltransferase binding (GO:0035035), protein binding (GO:0005515)

GO Cellular Component (14): histone acetyltransferase complex (GO:0000123), kinetochore (GO:0000776), spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), microtubule (GO:0005874), NSL complex (GO:0044545), MLL1 complex (GO:0071339), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), H4 histone acetyltransferase complex (GO:1902562)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1
Gene expression (Transcription)	1
Chromatin organization	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
intracellular membrane-bounded organelle	2
cellular component organization	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
mitochondrial transcription	1
regulation of mitochondrial gene expression	1
enzyme binding	1
binding	1
chromatin	1
protein acetyltransferase complex	1
condensed chromosome, centromeric region	1
supramolecular complex	1
spindle	1
nuclear lumen	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
H4 histone acetyltransferase complex	1
MLL1/2 complex	1
chromosomal region	1
intracellular anatomical structure	1
histone acetyltransferase complex	1

Protein interactions and networks

STRING

1301 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KANSL1	PHF20	Q9BVI0	952
KANSL1	STH	Q8IWL8	904
KANSL1	MCRS1	Q96EZ8	888
KANSL1	KANSL3	Q9P2N6	888
KANSL1	KANSL2	Q9H9L4	877
KANSL1	CRHR1	P34998	858
KANSL1	KAT8	Q9H7Z6	844
KANSL1	WDR5	P61964	824
KANSL1	MAPT	P10636	785
KANSL1	ARL17A	Q8IVW1	769
KANSL1	ARL17B	I3L3L1	768
KANSL1	LRRC37A	A6NMS7	730
KANSL1	LRRC37A3	O60309	724
KANSL1	WNT3	P56703	678
KANSL1	LRRC37A2	A6NM11	677

IntAct

127 interactions, top by confidence:

A	B	Type	Score
KANSL1	WDR5	psi-mi:“MI:0407”(direct interaction)	0.950
WDR5	KANSL1	psi-mi:“MI:0915”(physical association)	0.950
WDR5	KMT2D	psi-mi:“MI:0914”(association)	0.910
KANSL1	KRT15	psi-mi:“MI:0915”(physical association)	0.740
CALCOCO2	KANSL1	psi-mi:“MI:0915”(physical association)	0.740
TFIP11	KANSL1	psi-mi:“MI:0915”(physical association)	0.740
KANSL1	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.740
KRT15	KANSL1	psi-mi:“MI:0915”(physical association)	0.740
KANSL1	TFIP11	psi-mi:“MI:0915”(physical association)	0.740
WDR5	H3C1	psi-mi:“MI:0915”(physical association)	0.740
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
KANSL1	TRIM27	psi-mi:“MI:0915”(physical association)	0.670
NUP62	KANSL1	psi-mi:“MI:0915”(physical association)	0.670
KANSL1	CDR2	psi-mi:“MI:0915”(physical association)	0.670
GOLGA2	KANSL1	psi-mi:“MI:0915”(physical association)	0.670
KANSL1	CEP70	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (143): KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid), KANSL1 (Two-hybrid)

ESM2 similar proteins: A1L1F6, A2A891, A5GFT6, A5PLL1, A7XYJ6, B7ZS37, D4A666, E1B7L7, E7F888, E9Q2Z1, F1LMN3, F1QZ88, O35914, O60296, O70240, O88566, P0C6C1, P57095, P78312, Q08AZ1, Q12766, Q3UUF8, Q53TQ3, Q566I1, Q58FA4, Q5DTH5, Q5PQ89, Q5RJ80, Q5ZJ69, Q66JY2, Q68FE9, Q69ZF8, Q6ZSZ6, Q6ZU65, Q7YR76, Q7Z3B3, Q80TG1, Q8BLB8, Q8C966, Q8CGI1

Diamond homologs: A0AUZ9, Q7Z3B3, Q80TG1, Q5DTI6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KANSL1	“form complex”	“NSL histone acetyltransferase”	binding
KANSL1	up-regulates	Microtubule_polimerization
KANSL1	up-regulates	Chromosome_segregation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of WDR5-containing histone-modifying complexes	11	64.9×	2e-15
Epigenetic regulation by WDR5-containing histone modifying complexes	6	20.6×	9e-05
Formation of the beta-catenin:TCF transactivating complex	5	13.4×	2e-03
HATs acetylate histones	7	12.3×	2e-04
Activation of anterior HOX genes in hindbrain development during early embryogenesis	6	12.2×	6e-04
Chromatin modifying enzymes	7	11.2×	3e-04
Chromatin organization	6	10.9×	1e-03
Epigenetic regulation of gene expression	6	9.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin organization	6	9.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1509 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	77
Likely pathogenic	42
Uncertain significance	541
Likely benign	489
Benign	137

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071483	NM_015443.4(KANSL1):c.1657_1658insTTGTAT (p.Gln553delinsLeuValTer)	Pathogenic
1164057	NM_015443.4(KANSL1):c.501_511dup (p.Asp171fs)	Pathogenic
1164058	NM_015443.4(KANSL1):c.1420C>T (p.Arg474Cys)	Pathogenic
1184122	NM_015443.4(KANSL1):c.788del (p.Leu263fs)	Pathogenic
1208235	NM_015443.4(KANSL1):c.699dup (p.Val234fs)	Pathogenic
1212041	NM_015443.4(KANSL1):c.1726C>T (p.Arg576Ter)	Pathogenic
1299570	NM_015443.4(KANSL1):c.1849-26_1871del	Pathogenic
1334513	NM_015443.4(KANSL1):c.1328dup (p.Ala444fs)	Pathogenic
1410323	NC_000017.10:g.(?44159787)(44159928_?)dup	Pathogenic
1436579	NM_015443.4(KANSL1):c.2831dup (p.Ser945fs)	Pathogenic
1683960	NM_015443.4(KANSL1):c.2470C>T (p.Arg824Ter)	Pathogenic
1685895	NM_015443.4(KANSL1):c.2105del (p.Lys702fs)	Pathogenic
1698373	NM_015443.4:c.1431+1_1432-1del	Pathogenic
1700178	NM_015443.4(KANSL1):c.1110del (p.Phe370_Leu371insTer)	Pathogenic
1706573	NM_015443.4(KANSL1):c.1485_1488del (p.Leu496fs)	Pathogenic
1800574	NM_015443.4(KANSL1):c.1220C>G (p.Ser407Ter)	Pathogenic
205795	NM_015443.4(KANSL1):c.2203+1G>A	Pathogenic
2108108	NM_015443.4(KANSL1):c.2130del (p.Met711fs)	Pathogenic
2232486	NM_015443.4(KANSL1):c.2020+1G>A	Pathogenic
2277959	NM_015443.4(KANSL1):c.2519C>A (p.Ser840Ter)	Pathogenic
2441965	NM_015443.4(KANSL1):c.2772_2776del (p.Cys924_Glu926delinsTer)	Pathogenic
2443573	NM_015443.4(KANSL1):c.1944dup (p.His649fs)	Pathogenic
2444608	NM_015443.4(KANSL1):c.1384C>T (p.Arg462Ter)	Pathogenic
2446025	NM_015443.4(KANSL1):c.1802dup (p.Arg602fs)	Pathogenic
2577955	NM_015443.4(KANSL1):c.2109dup (p.Ser704fs)	Pathogenic
265688	NM_015443.4(KANSL1):c.1532del (p.Lys510_Leu511insTer)	Pathogenic
2798791	NM_015443.4(KANSL1):c.2342del (p.Pro781fs)	Pathogenic
2821971	NM_015443.4(KANSL1):c.2664del (p.Ser889fs)	Pathogenic
2863434	NM_015443.4(KANSL1):c.2104A>T (p.Lys702Ter)	Pathogenic
31693	NM_015443.4(KANSL1):c.1816C>T (p.Arg606Ter)	Pathogenic

SpliceAI

3830 predictions. Top by Δscore:

Variant	Effect	Δscore
17:46031700:CAGA:C	acceptor_gain	1.0000
17:46031704:C:CC	acceptor_gain	1.0000
17:46038532:ACTT:A	donor_loss	1.0000
17:46038533:CTT:C	donor_loss	1.0000
17:46038534:TTACC:T	donor_loss	1.0000
17:46038535:TACCG:T	donor_loss	1.0000
17:46038536:A:AC	donor_gain	1.0000
17:46038536:A:T	donor_loss	1.0000
17:46038537:C:CG	donor_gain	1.0000
17:46038537:CCGA:C	donor_gain	1.0000
17:46038537:CCGAT:C	donor_gain	1.0000
17:46038682:CAACA:C	acceptor_gain	1.0000
17:46038683:AACA:A	acceptor_gain	1.0000
17:46038684:ACACT:A	acceptor_loss	1.0000
17:46038685:CA:C	acceptor_gain	1.0000
17:46038686:AC:A	acceptor_loss	1.0000
17:46038687:C:CC	acceptor_gain	1.0000
17:46038687:C:CG	acceptor_loss	1.0000
17:46038697:C:CT	acceptor_gain	1.0000
17:46038698:A:T	acceptor_gain	1.0000
17:46038700:C:CT	acceptor_gain	1.0000
17:46038701:A:T	acceptor_gain	1.0000
17:46039211:CAGCT:C	acceptor_gain	1.0000
17:46039216:C:CC	acceptor_gain	1.0000
17:46039701:CTGG:C	donor_gain	1.0000
17:46039746:CGAG:C	donor_gain	1.0000
17:46050532:CCAT:C	donor_gain	1.0000
17:46050703:ACCT:A	acceptor_loss	1.0000
17:46050705:C:CC	acceptor_gain	1.0000
17:46050705:CTGT:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000048091 (17:46043813 C>A), RS1000052762 (17:46055084 C>G,T), RS1000093777 (17:46191396 C>A,G,T), RS1000109765 (17:46119801 T>A,C), RS1000134156 (17:46032610 T>A,C), RS1000136190 (17:46180245 C>T), RS1000146089 (17:46191177 C>T), RS1000149675 (17:46061757 T>G), RS1000165716 (17:46097222 C>T), RS1000193454 (17:46080425 C>T), RS1000198248 (17:46171657 T>C), RS1000204284 (17:46076699 C>T), RS1000228069 (17:46064065 A>AC), RS1000230050 (17:46213588 G>A), RS1000232456 (17:46149871 A>T)

Disease associations

OMIM: gene MIM:612452 | disease phenotypes: MIM:610443, MIM:123100, MIM:619681, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
Koolen-de Vries syndrome	Definitive	Autosomal dominant
Koolen-de Vries syndrome due to a point mutation	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Koolen-de Vries syndrome	Definitive	AD

Mondo (7): Koolen-de Vries syndrome (MONDO:0012496), craniosynostosis (MONDO:0015469), intellectual disability (MONDO:0001071), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), primary ovarian failure (MONDO:0005387), congenital myopathy (MONDO:0019952), Koolen-de Vries syndrome due to a point mutation (MONDO:0018217)

Orphanet (5): Koolen-De Vries syndrome (Orphanet:96169), Craniosynostosis (Orphanet:1531), Congenital myopathy (Orphanet:97245), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

81 total (30 of 81 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000189	Narrow palate
HP:0000194	Open mouth
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000337	Broad forehead
HP:0000348	High forehead
HP:0000396	Overfolded helix
HP:0000400	Macrotia
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000447	Pear-shaped nose
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000687	Widely spaced teeth
HP:0000739	Anxiety

GWAS associations

85 associations (top):

Study	Trait	p-value
GCST000528_6	Parkinson’s disease	2.000000e-16
GCST001974_3	Idiopathic pulmonary fibrosis	6.000000e-09
GCST002817_27	Alzheimer’s disease in APOE e4- carriers	6.000000e-09
GCST003174_21	Sense of smell	8.000000e-06
GCST003174_8	Sense of smell	7.000000e-06
GCST003983_9	Male-pattern baldness	8.000000e-20
GCST004077_11	Cognitive function	7.000000e-07
GCST004077_12	Cognitive function	7.000000e-07
GCST004183_3	Lung function (FEV1)	1.000000e-13
GCST004184_6	Lung function (FVC)	7.000000e-13
GCST004600_145	Eosinophil percentage of white cells	9.000000e-24
GCST004602_294	Mean corpuscular volume	2.000000e-09
GCST004606_34	Eosinophil count	2.000000e-18
GCST004611_128	High light scatter reticulocyte count	2.000000e-16
GCST004612_76	High light scatter reticulocyte percentage of red cells	3.000000e-11
GCST004617_123	Eosinophil percentage of granulocytes	2.000000e-25
GCST004619_184	Reticulocyte fraction of red cells	6.000000e-10
GCST004622_55	Reticulocyte count	1.000000e-17
GCST004623_85	Neutrophil percentage of granulocytes	7.000000e-25
GCST004624_15	Sum eosinophil basophil counts	4.000000e-16
GCST004630_216	Mean corpuscular hemoglobin	5.000000e-10
GCST004632_7	Lymphocyte percentage of white cells	5.000000e-13
GCST004633_2	Neutrophil percentage of white cells	9.000000e-15
GCST004902_11	Parkinson’s disease	1.000000e-68
GCST004988_669	Breast cancer	7.000000e-13
GCST005142_43	Cognitive ability	1.000000e-08
GCST005232_131	Neuroticism	8.000000e-26
GCST005235_13	Hand grip strength	1.000000e-09
GCST005993_15	Mean corpuscular hemoglobin	2.000000e-21
GCST005996_4	Red blood cell count	2.000000e-15

EFO canonical traits (37, from GWAS)

EFO ID	Trait name
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004337	intelligence
EFO:0004314	forced expiratory volume
EFO:0004312	vital capacity
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007986	reticulocyte count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0007994	neutrophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007660	neuroticism measurement
EFO:0006941	grip strength measurement
EFO:0004305	erythrocyte count
EFO:0008393	reaction time measurement
EFO:0009458	alcohol use disorder measurement
EFO:0009188	Red cell distribution width
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0009902	handedness
EFO:0009695	household income
EFO:0004509	hemoglobin measurement
EFO:0004641	white matter integrity
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0004918	age at diagnosis

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1528072	KANSL1		0.00	0
rs2532292	KANSL1		0.00	0
rs1078997	KANSL1		0.00	0
rs7521	KANSL1, MAPT		0.00	0

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects expression, decreases expression	3
trichostatin A	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
Irinotecan	affects response to substance, affects cotreatment	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	affects expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Fluorouracil	affects response to substance, affects cotreatment	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Particulate Matter	increases abundance, affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
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
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
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
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
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
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
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)
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type