KIRREL3

Summary

KIRREL3 (kirre like nephrin family adhesion molecule 3, HGNC:23204) is a protein-coding gene on chromosome 11q24.2, encoding Kin of IRRE-like protein 3 (Q8IZU9). Synaptic adhesion molecule required for the formation of target-specific synapses.

The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. The cytoplasmic domains of these proteins interact with the C-terminus of podocin, also expressed in the podocytes, cells involved in ensuring size- and charge-selective ultrafiltration. The protein encoded by this gene is a synaptic cell adhesion molecule with multiple extracellular immunoglobulin-like domains and a cytoplasmic PDZ domain-binding motif. Mutations in this gene are associated with several neurological and cognitive disorders. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 84623 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant non-syndromic intellectual disability (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 190 total — 1 pathogenic, 3 likely-pathogenic
• MANE Select transcript: NM_032531

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23204
Approved symbol	KIRREL3
Name	kirre like nephrin family adhesion molecule 3
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	NEPH2, KIAA1867, KIRRE
Ensembl gene	ENSG00000149571
Ensembl biotype	protein_coding
OMIM	607761
Entrez	84623

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding_CDS_not_defined, 3 protein_coding, 1 retained_intron

ENST00000525144, ENST00000525704, ENST00000526519, ENST00000526764, ENST00000529097, ENST00000532647, ENST00000533026, ENST00000547738, ENST00000549874

RefSeq mRNA: 3 — MANE Select: NM_032531 NM_001161707, NM_001301097, NM_032531

CCDS: CCDS53723, CCDS55796, CCDS73413

Canonical transcript exons

ENST00000525144 — 17 exons

Exon	Start	End
ENSE00000991378	126526538	126526687
ENSE00000991379	126521315	126521464
ENSE00000991382	126449009	126449157
ENSE00000991383	126446759	126446886
ENSE00000991384	126444979	126445105
ENSE00000995026	126456349	126456454
ENSE00000995028	126473309	126473466
ENSE00000995029	126463157	126463307
ENSE00001094072	126425638	126425724
ENSE00001094089	126435268	126435303
ENSE00001130468	126423358	126425023
ENSE00002376031	127000455	127000770
ENSE00003461741	126436811	126437009
ENSE00003523696	126562835	126562912
ENSE00003653618	126429179	126429288
ENSE00003694601	126440449	126440549
ENSE00003720646	126431419	126431526

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 91.04.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2743 / max 641.9583, expressed in 665 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123059	1.9882	358
123060	1.0271	322
123066	0.7282	176
123062	0.6734	177
123061	0.3918	141
206492	0.1271	54
123034	0.0849	14
123067	0.0767	47
123064	0.0708	14
123065	0.0541	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	91.04	gold quality
nucleus accumbens	UBERON:0001882	88.25	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.15	gold quality
prefrontal cortex	UBERON:0000451	87.08	gold quality
right frontal lobe	UBERON:0002810	86.88	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.56	gold quality
left ventricle myocardium	UBERON:0006566	86.54	gold quality
caudate nucleus	UBERON:0001873	86.44	gold quality
kidney epithelium	UBERON:0004819	86.37	gold quality
putamen	UBERON:0001874	85.84	gold quality
frontal cortex	UBERON:0001870	85.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.30	gold quality
neocortex	UBERON:0001950	84.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.48	gold quality
endothelial cell	CL:0000115	84.38	gold quality
cerebral cortex	UBERON:0000956	83.56	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.00	gold quality
entorhinal cortex	UBERON:0002728	82.84	gold quality
anterior cingulate cortex	UBERON:0009835	82.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.53	gold quality
primary visual cortex	UBERON:0002436	82.44	gold quality
temporal lobe	UBERON:0001871	82.37	gold quality
amygdala	UBERON:0001876	82.05	gold quality
spinal cord	UBERON:0002240	81.64	gold quality
cerebellar cortex	UBERON:0002129	81.42	gold quality
cerebellar hemisphere	UBERON:0002245	81.42	gold quality
cortical plate	UBERON:0005343	81.07	gold quality
Ammon’s horn	UBERON:0001954	81.05	gold quality
superior frontal gyrus	UBERON:0002661	81.05	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.03	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	3518.44
E-MTAB-11268	yes	1823.69
E-CURD-119	yes	23.97
E-ANND-3	no	4.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting KIRREL3, 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-6876-5P	100.00	67.68	2126
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-581	98.39	67.42	835
HSA-MIR-7111-3P	97.80	66.75	1467

Literature-anchored findings (GeneRIF, showing 5)

• Alterations in KIRREL3 in patients with mild to severe intellectual disability are reported. (PMID:19012874)
• Results presented demonstrate for the first time that there are at least 3 splice variants of Kirrel3 expressed in adult human skeletal muscle, two of which have never previously been identified in human muscle. (PMID:25488023)
• KIRREL3 interacting proteins MAP1B and MYO16 are potential candidates for intellectual disability and autism spectrum disorder. (PMID:25902260)
• Preliminary study on the role and mechanism of KIRREL3 in the development of esophageal squamous cell carcinoma. (PMID:35863131)
• Modular Splicing Is Linked to Evolution in the Synapse-Specificity Molecule Kirrel3. (PMID:37977826)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	kirrel3a	ENSDARG00000075806
danio_rerio		ENSDARG00000113833
danio_rerio	KIRREL3	ENSDARG00000115903
mus_musculus	Kirrel3	ENSMUSG00000032036
rattus_norvegicus	Kirrel3	ENSRNOG00000009772
drosophila_melanogaster	ed	FBGN0000547
drosophila_melanogaster	rst	FBGN0003285
drosophila_melanogaster	kirre	FBGN0028369
drosophila_melanogaster	fred	FBGN0051774
caenorhabditis_elegans		WBGENE00006365
caenorhabditis_elegans		WBGENE00018215

Paralogs (3): KIRREL2 (ENSG00000126259), NPHS1 (ENSG00000161270), KIRREL1 (ENSG00000183853)

Protein

Protein identifiers

Kin of IRRE-like protein 3 — Q8IZU9 (reviewed: Q8IZU9)

Alternative names: Kin of irregular chiasm-like protein 3, Nephrin-like protein 2

All UniProt accessions (2): Q8IZU9, E9PRX9

UniProt curated annotations — full annotation on UniProt →

Function. Synaptic adhesion molecule required for the formation of target-specific synapses. Required for formation of target-specific synapses at hippocampal mossy fiber synapses. Required for formation of mossy fiber filopodia, the synaptic structures connecting dentate granule and GABA neurons. Probably acts as a homophilic adhesion molecule that promotes trans-cellular interactions and stabilize mossy fiber filipodia contact and subsequent synapse formation. Required for the coalescence of vomeronasal sensory neuron axons. May be involved in the hematopoietic supportive capacity of stroma cells; the secreted extracellular domain is directly responsible for supporting hematopoietic stem cells.

Subunit / interactions. Homodimer; mediates homophilic interactions to promote cell adhesion. Interacts with NPHS1; forms heterodimers with NPHS1. Interacts with NPHS2/podocin (via the C-terminus). Interacts with CASK. Interacts (via extracellular region) with MAP1B. Interacts (via extracellular region) with MYO16. Interacts (via intracellular region) with ATP1B1. Interacts (via intracellular region) with SHMT2. Interacts (via intracellular region) with UFC1.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Expressed in fetal and adult brain. Also expressed in kidney, specifically in podocytes of kidney glomeruli. Also expressed in skeletal muscle.

Post-translational modifications. Undergoes proteolysis by a metalloprotease and gives rise to a soluble form.

Disease relevance. A chromosomal aberration involving KIRREL3 and CDH15 is found in a patient with severe intellectual disability and dysmorphic facial features. Translocation t(11;16)(q24.2;q24).

Similarity. Belongs to the immunoglobulin superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZU9-1	1, Kirrel3 A	yes
Q8IZU9-2	2, Kirrel3 B

RefSeq proteins (3): NP_001155179, NP_001288026, NP_115920* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051275	Cell_adhesion_signaling	Family

Pfam: PF07679, PF08205, PF13927

UniProt features (37 total): strand 8, domain 5, disulfide bond 5, glycosylation site 4, sequence variant 3, chain 2, compositionally biased region 2, splice variant 2, topological domain 2, signal peptide 1, region of interest 1, helix 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CRY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZU9-F1	72.24	0.49

Functional residue map

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

Disulfide bonds (5): 69–127, 170–227, 271–314, 356–398, 440–499

Glycosylation sites (4): 167, 253, 324, 498

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373753	Nephrin family interactions
R-HSA-1500931	Cell-Cell communication

MSigDB gene sets: 136 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_ADHESION, IRF7_01, GOBP_CELL_JUNCTION_ORGANIZATION, MODULE_205, GOBP_NEURAL_NUCLEUS_DEVELOPMENT, GOBP_HIPPOCAMPUS_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, GOBP_GLOMERULUS_DEVELOPMENT, HFH4_01

GO Biological Process (10): neuron migration (GO:0001764), inter-male aggressive behavior (GO:0002121), homophilic cell-cell adhesion (GO:0007156), synapse assembly (GO:0007416), principal sensory nucleus of trigeminal nerve development (GO:0021740), hippocampus development (GO:0021766), hemopoiesis (GO:0030097), neuron projection morphogenesis (GO:0048812), glomerulus morphogenesis (GO:0072102), cell-cell adhesion (GO:0098609)

GO Molecular Function (2): cell adhesion molecule binding (GO:0050839), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), synaptic vesicle (GO:0008021), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), dendritic shaft (GO:0043198)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
neuron projection	2
cell migration	1
generation of neurons	1
aggressive behavior	1
cell-cell adhesion	1
nervous system development	1
cell junction assembly	1
synapse organization	1
trigeminal sensory nucleus development	1
pallium development	1
limbic system development	1
anatomical structure development	1
cell development	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
anatomical structure morphogenesis	1
glomerulus development	1
cell adhesion	1
protein binding	1
binding	1
membrane	1
cell periphery	1
anchoring junction	1
exocytic vesicle	1
presynapse	1
dendritic tree	1
dendrite	1

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIRREL3	NPHS1	O60500	943
KIRREL3	NPHS2	Q9NP85	937
KIRREL3	CD2AP	Q9Y5K6	900
KIRREL3	KIRREL1	Q96J84	840
KIRREL3	CDH15	P55291	769
KIRREL3	PDZK1	Q5T2W1	765
KIRREL3	ITK	Q08881	668
KIRREL3	SCN10A	Q9Y5Y9	630
KIRREL3	BCL2A1	Q16548	544
KIRREL3	DLG4	P78352	539
KIRREL3	EML4	Q9HC35	523
KIRREL3	GRB2	P29354	511
KIRREL3	FAT1	Q14517	490
KIRREL3	CNTN5	O94779	488
KIRREL3	TJP1	Q07157	478

IntAct

39 interactions, top by confidence:

A	B	Type	Score
KIRREL3	MAP1B	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	MYO16	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	ATP1B1	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	UFC1	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	SHMT2	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	MAP1B	psi-mi:“MI:0403”(colocalization)	0.540
KIRREL3	MYO16	psi-mi:“MI:0403”(colocalization)	0.540
KIRREL3	ATP1B1	psi-mi:“MI:0403”(colocalization)	0.540
KIRREL3	UFC1	psi-mi:“MI:0403”(colocalization)	0.540
KIRREL3	SHMT2	psi-mi:“MI:0403”(colocalization)	0.540
EZR	KIRREL3	psi-mi:“MI:0407”(direct interaction)	0.540
RDX	KIRREL3	psi-mi:“MI:0407”(direct interaction)	0.540
KIRREL3	RDX	psi-mi:“MI:0915”(physical association)	0.540
KIRREL3	CASK	psi-mi:“MI:0403”(colocalization)	0.430
KIRREL3	Map1b	psi-mi:“MI:0915”(physical association)	0.400
EZR	E	psi-mi:“MI:0915”(physical association)	0.400
EZR		psi-mi:“MI:0915”(physical association)	0.400
KIRREL3		psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): KIRREL3 (Affinity Capture-RNA), KIRREL3 (Affinity Capture-MS), KIRREL3 (Protein-peptide)

ESM2 similar proteins: A0A0R4IGV4, A0A8M2B818, B0JYH6, F1LW30, O35112, O46634, O46651, P0C673, P17948, P26453, P35969, P42292, P53767, Q08DK1, Q13740, Q15198, Q1WIM2, Q2PFX1, Q504C1, Q58EG3, Q5DX21, Q5FWR8, Q5R412, Q5RJP7, Q5U2P2, Q5VJ70, Q61490, Q6DJ83, Q6PE55, Q6UXZ4, Q6X936, Q7T2Z5, Q7TSN7, Q80W68, Q8BLQ9, Q8BR86, Q8IZU9, Q8K1S2, Q8N3J6, Q8QHL3

Diamond homologs: A8WQH2, O94898, P12960, P14781, P19320, P29533, P29534, P46630, P52583, P70232, Q12860, Q15746, Q1ENI8, Q24372, Q28106, Q28260, Q29RR6, Q5STE3, Q6MZW2, Q6PDN3, Q7L985, Q8BQC3, Q8BR86, Q8IVU1, Q8IZU9, A2AAJ9, A2AJ76, P98160, Q2EY13, Q5VST9, Q6UWL6, Q6X936, Q7TSU7, Q80W68, Q8HW98, Q8IUL8, Q8JG38, Q96J84, D3ZB51, E9PZ19

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KIRREL3	up-regulates	Synaptic_plasticity
KIRREL3	“up-regulates activity”	CASK	binding
KIRREL3	“up-regulates activity”	DLG4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	119
Likely benign	40
Benign	14

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
625594	GRCh37/hg19 11q24.2-25(chr11:125446101-134904063)	Pathogenic
375632	NM_032531.4(KIRREL3):c.2019G>A (p.Met673Ile)	Likely pathogenic
422138	NM_032531.4(KIRREL3):c.997+1G>A	Likely pathogenic
992844	NM_032531.4(KIRREL3):c.941G>T (p.Cys314Phe)	Likely pathogenic

SpliceAI

6150 predictions. Top by Δscore:

Variant	Effect	Δscore
11:126425021:GTCC:G	acceptor_loss	1.0000
11:126425022:TCC:T	acceptor_loss	1.0000
11:126425023:CCT:C	acceptor_loss	1.0000
11:126425024:C:CA	acceptor_loss	1.0000
11:126425024:C:CC	acceptor_gain	1.0000
11:126425632:TCTTA:T	donor_loss	1.0000
11:126425633:CTTAC:C	donor_loss	1.0000
11:126425634:TTA:T	donor_loss	1.0000
11:126425635:TAC:T	donor_loss	1.0000
11:126425636:A:AC	donor_gain	1.0000
11:126425637:C:CC	donor_gain	1.0000
11:126425637:C:CT	donor_loss	1.0000
11:126425637:CCTT:C	donor_gain	1.0000
11:126425720:TCCAT:T	acceptor_gain	1.0000
11:126425721:CCAT:C	acceptor_gain	1.0000
11:126425721:CCATC:C	acceptor_gain	1.0000
11:126425722:CAT:C	acceptor_gain	1.0000
11:126425722:CATC:C	acceptor_gain	1.0000
11:126425723:AT:A	acceptor_gain	1.0000
11:126425724:TCTG:T	acceptor_loss	1.0000
11:126425725:C:CC	acceptor_gain	1.0000
11:126429173:TCTTA:T	donor_loss	1.0000
11:126429174:CTTA:C	donor_loss	1.0000
11:126429175:TTA:T	donor_loss	1.0000
11:126429176:TA:T	donor_loss	1.0000
11:126429177:A:AC	donor_gain	1.0000
11:126429177:A:AG	donor_loss	1.0000
11:126429178:C:CC	donor_gain	1.0000
11:126429178:CCAT:C	donor_gain	1.0000
11:126429285:AGAT:A	acceptor_gain	1.0000

AlphaMissense

5074 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:126436854:G:C	N503K	1.000
11:126436854:G:T	N503K	1.000
11:126436855:T:A	N503I	1.000
11:126436856:T:A	N503Y	1.000
11:126436857:C:A	W502C	1.000
11:126436857:C:G	W502C	1.000
11:126436861:G:T	A501D	1.000
11:126436862:C:G	A501P	1.000
11:126436866:G:C	C499W	1.000
11:126436867:C:A	C499F	1.000
11:126436867:C:G	C499S	1.000
11:126436867:C:T	C499Y	1.000
11:126436868:A:G	C499R	1.000
11:126436868:A:T	C499S	1.000
11:126436874:A:C	Y497D	1.000
11:126436888:T:A	D492V	1.000
11:126436915:A:G	L483P	1.000
11:126436922:A:G	S481P	1.000
11:126436998:C:A	W455C	1.000
11:126436998:C:G	W455C	1.000
11:126437003:A:G	S454P	1.000
11:126437004:C:A	W453C	1.000
11:126437004:C:G	W453C	1.000
11:126437005:C:G	W453S	1.000
11:126437006:A:G	W453R	1.000
11:126437006:A:T	W453R	1.000
11:126440482:G:C	C440W	1.000
11:126440483:C:A	C440F	1.000
11:126440483:C:G	C440S	1.000
11:126440483:C:T	C440Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000007507 (11:126867637 T>C), RS1000012754 (11:126496611 G>A), RS1000019543 (11:126649157 T>C), RS1000024241 (11:126505699 C>A), RS1000025092 (11:126480863 G>A), RS1000030987 (11:126433694 T>G), RS1000037073 (11:126914075 T>C), RS1000038251 (11:126881329 T>A), RS1000039070 (11:126897274 G>C), RS1000042398 (11:126655577 G>T), RS1000044935 (11:126521415 G>A,T), RS1000047661 (11:126798870 G>T), RS1000058005 (11:126797650 G>A,T), RS1000061160 (11:126833868 G>A), RS1000066921 (11:126747000 C>T)

Disease associations

OMIM: gene MIM:607761 | disease phenotypes: MIM:612581, MIM:147791

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
intellectual disability, autosomal dominant 4	Limited	Unknown
complex neurodevelopmental disorder	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Disputed	AD

Mondo (6): intellectual disability, autosomal dominant 4 (MONDO:0012947), autism spectrum disorder (MONDO:0005258), Jacobsen syndrome (MONDO:0007838), intellectual disability (MONDO:0001071), autosomal dominant non-syndromic intellectual disability (MONDO:0015802), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Jacobsen syndrome (Orphanet:2308), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000189_17	Protein quantitative trait loci	1.000000e-06
GCST000253_22	Attention deficit hyperactivity disorder and conduct disorder	5.000000e-06
GCST000618_21	Response to antipsychotic treatment	3.000000e-06
GCST001585_13	Breast size	6.000000e-06
GCST002013_7	Menarche (age at onset)	2.000000e-06
GCST002589_16	Hippocampal sclerosis	7.000000e-06
GCST003944_16	Hepcidin/ferritin ratio	2.000000e-06
GCST007325_258	General risk tolerance (MTAG)	3.000000e-09
GCST007576_158	Chronotype	9.000000e-10
GCST007624_2	Positive urgency	2.000000e-07
GCST008144_5	Fasting plasma glucose	2.000000e-06
GCST008162_71	Hip circumference	1.000000e-06
GCST008162_88	Hip circumference	9.000000e-06
GCST010133_3	Lamb consumption	2.000000e-11
GCST010135_34	Oily fish consumption	8.000000e-09
GCST010140_24	Pork consumption	8.000000e-09
GCST010143_38	Meat-related diet	2.000000e-08
GCST010242_161	HDL cholesterol levels	9.000000e-12
GCST010396_217	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-06
GCST010984_29	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	2.000000e-10
GCST010989_32	Body size at age 10	7.000000e-12
GCST011353_13	Serum alkaline phosphatase levels	5.000000e-62
GCST012490_531	Femur bone mineral density x serum urate levels interaction	3.000000e-09
GCST90011900_62	Serum alkaline phosphatase levels	5.000000e-182

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0007901	hepcidin:ferritin ratio
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0008111	diet measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004533	alkaline phosphatase measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C567240	Mental Retardation, Autosomal Dominant 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression, affects methylation, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Cisplatin	affects cotreatment, decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder