LHX2

Summary

LHX2 (LIM homeobox 2, HGNC:6594) is a protein-coding gene on chromosome 9q33.3, encoding LIM/homeobox protein Lhx2 (P50458). Acts as a transcriptional activator.

This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator. The protein can recapitulate or rescue phenotypes in Drosophila caused by a related protein, suggesting conservation of function during evolution.

Source: NCBI Gene 9355 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 73 total — 6 pathogenic, 1 likely-pathogenic
• Transcription factor: yes — 46 downstream targets (CollecTRI)
• MANE Select transcript: NM_004789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6594
Approved symbol	LHX2
Name	LIM homeobox 2
Location	9q33.3
Locus type	gene with protein product
Status	Approved
Aliases	LH-2, hLhx2
Ensembl gene	ENSG00000106689
Ensembl biotype	protein_coding
OMIM	603759
Entrez	9355

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000373615, ENST00000446480, ENST00000488674, ENST00000560961

RefSeq mRNA: 1 — MANE Select: NM_004789 NM_004789

CCDS: CCDS6853

Canonical transcript exons

ENST00000373615 — 5 exons

Exon	Start	End
ENSE00000726665	124015122	124015525
ENSE00001461029	124011768	124012468
ENSE00003469146	124032420	124033301
ENSE00003700778	124021099	124021304
ENSE00003715988	124013961	124014163

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 99.68.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4616 / max 424.5114, expressed in 576 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98446	3.4908	486
98445	1.7458	306
98447	0.8906	171
98448	0.1704	73
98450	0.1032	43
98449	0.0371	13
205612	0.0238	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.68	gold quality
hair follicle	UBERON:0002073	99.58	gold quality
ganglionic eminence	UBERON:0004023	99.42	gold quality
sperm	CL:0000019	99.37	gold quality
pigmented layer of retina	UBERON:0001782	98.35	gold quality
endothelial cell	CL:0000115	98.27	gold quality
entorhinal cortex	UBERON:0002728	97.08	gold quality
middle temporal gyrus	UBERON:0002771	96.94	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.35	gold quality
temporal lobe	UBERON:0001871	96.25	gold quality
amygdala	UBERON:0001876	95.92	gold quality
primary visual cortex	UBERON:0002436	95.57	gold quality
postcentral gyrus	UBERON:0002581	95.53	gold quality
superior frontal gyrus	UBERON:0002661	95.49	gold quality
cingulate cortex	UBERON:0003027	95.38	gold quality
anterior cingulate cortex	UBERON:0009835	95.38	gold quality
parietal lobe	UBERON:0001872	95.35	gold quality
Ammon’s horn	UBERON:0001954	95.11	gold quality
male germ cell	CL:0000015	95.05	gold quality
occipital lobe	UBERON:0002021	94.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.77	gold quality
cerebral cortex	UBERON:0000956	94.49	gold quality
cortical plate	UBERON:0005343	94.41	gold quality
secondary oocyte	CL:0000655	94.10	gold quality
putamen	UBERON:0001874	94.10	gold quality
neocortex	UBERON:0001950	93.97	gold quality
prefrontal cortex	UBERON:0000451	93.72	gold quality
telencephalon	UBERON:0001893	93.72	gold quality
right frontal lobe	UBERON:0002810	93.70	gold quality
buccal mucosa cell	CL:0002336	93.61	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	53.03
E-GEOD-93593	yes	14.26
E-MTAB-10485	no	713.19
E-ANND-3	no	1.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

46 targets.

Target	Regulation
ADM
BIRC3
BTBD3	Activation
CAT
CD74
CDH1
CDKN2A
CGA	Activation
CXCL8
CYP19A1
FSHB
GFAP
GJA1
HHIP
HINT1
HLA-E
ITGAX
LHX2
LIM2
LMO3
MSX1	Activation
MSX2	Activation
MYF5	Activation
NOTCH1
OR10J5	Activation
OR52I2	Activation
OR6A2	Activation
OR8A1	Activation
PAX6	Unknown
PCYT1A

JASPAR motifs

Motif	Name	Family
MA0700.1	LHX2	HD-LIM
MA0700.2	LHX2	HD-LIM
MA0700.3	LHX2	HD-LIM

JASPAR matrix evidence (PMIDs): PMID:18585360, PMID:23332764

Upstream regulators (CollecTRI, top): ATF4, E2F1, HOXA5, LHX2, PAX6, TP53

miRNA regulators (miRDB)

74 targeting LHX2, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-651-5P	99.64	68.49	1104

Literature-anchored findings (GeneRIF, showing 17)

• A large cohort of patients with schizencephaly, some with features of septo-optic dysplasia, were sequenced for mutations in LHX2, HESX1 and SOX2. (PMID:20949537)
• Mutations in LHX2 do not represent a frequent cause of micro/anophthalmia. (PMID:21203406)
• These results suggest that if LHX2 is involved in pituitary hormone deficiency associated with posterior pituitary and ocular defects, it would be a rare cause of this disease condition. (PMID:22535646)
• This study demonistrated that LHx2 regulates the development of the forebrain hem system. (PMID:23307637)
• The findings indicate that LHX2 regulates the transcription of downstream intrinsic and extrinsic molecules that are essential for early neural differentiation. (PMID:23804753)
• The data indicate a dual role of Lhx2 during EMT and tumor progression: by inducing the expression of PDGF-B, Lhx2 provokes an autocrine PDGF-B/PDGFRbeta loop required for cell migration, invasion and metastatic dissemination (PMID:24423492)
• Results show that LHX2 is overexpressed in pancreatic ductal adenocarcinoma cells and is involved in promoting cancer cell proliferation and enhanced tumor development. (PMID:25324171)
• Lhx2 directly regulates tanycyte specification and differentiation in the hypothalamus. (PMID:25505333)
• Findings demonstrate that miR-1238 inhibit the proliferation of NSCLC cells at least partly via repression of LHX2, shedding light on the mechanistic interaction of miR-1238 and LHX2 in NSCLC carcinogenesis. (PMID:26189214)
• These data indicate that Lhx2 is capable of blocking proliferation of T-ALL-derived cells by both LMO2-dependent and -independent means. We propose Lhx2 as a new molecular tool for anti-T-ALL drug development. (PMID:29278703)
• LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells. (PMID:30765795)
• LHX2 promotes malignancy and inhibits autophagy via mTOR in osteosarcoma and is negatively regulated by miR-129-5p. (PMID:31724536)
• REGgamma regulates hair cycle by activating Lgr5 positive hair follicle stem cells. (PMID:33933312)
• LHX2 facilitates the progression of nasopharyngeal carcinoma via activation of the FGF1/FGFR axis. (PMID:35864158)
• The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration. (PMID:36649236)
• LHX2 haploinsufficiency causes a variable neurodevelopmental disorder. (PMID:37057675)
• LIM Homeobox 2 Increases Adhesion-Regulating Molecule 1 Transcription to Facilitate the Pathological Progression of Oxidized Low-Density Lipoprotein-Stimulated Atherosclerotic Cell Models. (PMID:37518356)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhx2b	ENSDARG00000031222
mus_musculus	Lhx2	ENSMUSG00000000247
rattus_norvegicus	Lhx2	ENSRNOG00000010551

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), LHX4 (ENSG00000121454), LMO2 (ENSG00000135363), ZFHX2 (ENSG00000136367), LMX1B (ENSG00000136944), ZFHX3 (ENSG00000140836), LMO4 (ENSG00000143013), LHX9 (ENSG00000143355), CRIP3 (ENSG00000146215), LHX8 (ENSG00000162624), LMX1A (ENSG00000162761), LMO1 (ENSG00000166407), CRIP2 (ENSG00000182809), CRIP1 (ENSG00000213145), LHX1 (ENSG00000273706)

Protein

Protein identifiers

LIM/homeobox protein Lhx2 — P50458 (reviewed: P50458)

All UniProt accessions (4): P50458, H0YM35, H7C0H1, U3KQT5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator. Stimulates the promoter of the alpha-glycoprotein gene. Transcriptional regulatory protein involved in the control of cell differentiation in developing lymphoid and neural cell types.

Subunit / interactions. Interacts (via LIM domains) with CITED2. Interacts with POU4F2.

Subcellular location. Nucleus.

Domain organisation. LIM domains are necessary for transcription activation.

RefSeq proteins (1): NP_004780* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001781	Znf_LIM	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (19 total): sequence conflict 8, compositionally biased region 3, region of interest 3, domain 2, chain 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50458-F1	67.03	0.31

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9752946	Expression and translocation of olfactory receptors
R-HSA-1266738	Developmental Biology
R-HSA-376176	Signaling by ROBO receptors
R-HSA-381753	Olfactory Signaling Pathway
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 262 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, CHOI_ATL_ACUTE_STAGE, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, BOYLAN_MULTIPLE_MYELOMA_PCA1_DN, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_NEURON_PROJECTION_EXTENSION, SP3_Q3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GROWTH, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP

GO Biological Process (24): neural tube closure (GO:0001843), hair follicle development (GO:0001942), regulation of transcription by RNA polymerase II (GO:0006357), axon guidance (GO:0007411), mesoderm development (GO:0007498), dorsal/ventral pattern formation (GO:0009953), olfactory bulb development (GO:0021772), telencephalon regionalization (GO:0021978), cerebral cortex development (GO:0021987), neuron differentiation (GO:0030182), maintenance of epithelial cell apical/basal polarity (GO:0045199), negative regulation of gene expression, epigenetic (GO:0045814), positive regulation of DNA-templated transcription (GO:0045893), axon extension (GO:0048675), negative regulation of neurogenesis (GO:0050768), retina development in camera-type eye (GO:0060041), positive regulation of neural precursor cell proliferation (GO:2000179), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), brain development (GO:0007420), telencephalon development (GO:0021537), neurogenesis (GO:0022008), positive regulation of transcription by RNA polymerase II (GO:0045944), anatomical structure formation involved in morphogenesis (GO:0048646)

GO Molecular Function (9): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), metal ion binding (GO:0046872), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by ROBO receptors	1
Olfactory Signaling Pathway	1
Axon guidance	1
Sensory Perception	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
axonogenesis	2
regionalization	2
DNA-templated transcription	2
binding	2
primary neural tube formation	1
tube closure	1
hair cycle process	1
skin epidermis development	1
transcription by RNA polymerase II	1
neuron projection guidance	1
tissue development	1
olfactory lobe development	1
telencephalon development	1
forebrain regionalization	1
pallium development	1
cell differentiation	1
generation of neurons	1
maintenance of apical/basal cell polarity	1
establishment or maintenance of epithelial cell apical/basal polarity	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
positive regulation of RNA biosynthetic process	1
neuron projection extension	1
negative regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
negative regulation of nervous system development	1
camera-type eye development	1
positive regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
central nervous system development	1
animal organ development	1
head development	1

Protein interactions and networks

STRING

2078 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHX2	LDB1	Q86U70	932
LHX2	LDB2	O43679	907
LHX2	CITED2	Q99967	858
LHX2	NEUROG2	Q9H2A3	749
LHX2	SIX3	O95343	742
LHX2	ASCL1	P50553	736
LHX2	RLIM	Q9NVW2	726
LHX2	NEUROG1	Q92886	714
LHX2	EBF1	Q9UH73	685
LHX2	ATOH1	Q92858	675
LHX2	FOXG1	P55315	673
LHX2	MSX1	P28360	667
LHX2	NEK6	Q9HC98	654
LHX2	DENND1A	Q8TEH3	640
LHX2	NEK7	Q8TDX7	635
LHX2	SOX3	P35714	635

IntAct

79 interactions, top by confidence:

A	B	Type	Score
SSBP3	LMX1B	psi-mi:“MI:0914”(association)	0.740
PYGO1	BCL9	psi-mi:“MI:0914”(association)	0.700
LDB1	LHX2	psi-mi:“MI:0915”(physical association)	0.590
LHX2	LGALSL	psi-mi:“MI:0915”(physical association)	0.560
LHX2	MORN3	psi-mi:“MI:0915”(physical association)	0.560
LHX2	PPIL1	psi-mi:“MI:0915”(physical association)	0.560
LHX2	POU4F2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	HOMER3	psi-mi:“MI:0915”(physical association)	0.560
LHX2	LDB1	psi-mi:“MI:0915”(physical association)	0.560
KHK	LHX2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	TCEANC	psi-mi:“MI:0915”(physical association)	0.560
LHX2	ZFP42	psi-mi:“MI:0915”(physical association)	0.560
LHX2	TRAPPC2L	psi-mi:“MI:0915”(physical association)	0.560
LHX2	FLYWCH1	psi-mi:“MI:0915”(physical association)	0.560
LHX2	ZNF511	psi-mi:“MI:0915”(physical association)	0.560
ARHGAP32	LHX2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	OSMR	psi-mi:“MI:0915”(physical association)	0.560
LHX2	BEND2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	TLK1	psi-mi:“MI:0915”(physical association)	0.560
LHX2	ANKS1A	psi-mi:“MI:0915”(physical association)	0.560
LHX2	TCP11L1	psi-mi:“MI:0915”(physical association)	0.560
UBTFL1	LHX2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	MORF4L1	psi-mi:“MI:0915”(physical association)	0.560
LHX2	LONRF1	psi-mi:“MI:0915”(physical association)	0.560
HOXC8	LHX2	psi-mi:“MI:0915”(physical association)	0.560
LHX2	LNX1	psi-mi:“MI:0915”(physical association)	0.560
SSBP4	LMX1B	psi-mi:“MI:0914”(association)	0.530
NFIA	LHX2	psi-mi:“MI:0915”(physical association)	0.470
NFIB	LHX2	psi-mi:“MI:0915”(physical association)	0.470
NFIC	LHX2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (190): LHX2 (Reconstituted Complex), CITED2 (Two-hybrid), LHX2 (Affinity Capture-MS), LHX2 (Affinity Capture-MS), LHX2 (Two-hybrid), LHX2 (Two-hybrid), LHX2 (Two-hybrid), LHX2 (Two-hybrid), LHX2 (Two-hybrid), LGALSL (Two-hybrid), ARHGAP32 (Two-hybrid), PPIL1 (Two-hybrid), KHK (Two-hybrid), MORN3 (Two-hybrid), OSMR (Two-hybrid)

ESM2 similar proteins: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, G5EEA1, P20154, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53411, P53412, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q1LWV4, Q5IS44, Q5IS89, Q68EY3

Diamond homologs: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, O14639, O35652, O60663, O88609, O94929, O97581, P20154, P25791, P25800, P25801, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50480, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53410, P53411, P53412, P53413, P53667, P53668

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
LDB1	“up-regulates activity”	LHX2	binding
LHX2	“down-regulates activity”	MSX1	binding
MSX1	“down-regulates activity”	LHX2	binding
LHX2	“up-regulates quantity by expression”	CGA	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	58
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3340743	NM_004789.4(LHX2):c.948C>G (p.Asn316Lys)	Pathogenic
3340939	NM_004789.4(LHX2):c.437G>A (p.Cys146Tyr)	Pathogenic
3342326	NM_004789.4(LHX2):c.289_293del (p.Lys96_Asp97insTer)	Pathogenic
3686831	NM_004789.4(LHX2):c.750del (p.Asp250fs)	Pathogenic
3781039	NM_004789.4(LHX2):c.673_694del (p.Pro225fs)	Pathogenic
4819122	NM_004789.4(LHX2):c.240C>A (p.Cys80Ter)	Pathogenic
2572331	NM_004789.4(LHX2):c.182_187delinsACCT (p.Ser61fs)	Likely pathogenic

SpliceAI

1140 predictions. Top by Δscore:

Variant	Effect	Δscore
9:124012465:GACG:G	donor_gain	1.0000
9:124012469:G:GG	donor_gain	1.0000
9:124013957:GCA:G	acceptor_loss	1.0000
9:124013958:CAG:C	acceptor_loss	1.0000
9:124013959:A:AG	acceptor_gain	1.0000
9:124013959:AGACC:A	acceptor_loss	1.0000
9:124013960:G:GG	acceptor_gain	1.0000
9:124013960:GAC:G	acceptor_gain	1.0000
9:124013960:GACC:G	acceptor_gain	1.0000
9:124013960:GACCA:G	acceptor_gain	1.0000
9:124014129:G:GT	donor_gain	1.0000
9:124014134:T:TA	donor_gain	1.0000
9:124014135:A:AA	donor_gain	1.0000
9:124014150:G:GT	donor_gain	1.0000
9:124014162:AG:A	donor_loss	1.0000
9:124014163:GG:G	donor_loss	1.0000
9:124014164:G:GA	donor_loss	1.0000
9:124014165:T:A	donor_loss	1.0000
9:124021094:CCTA:C	acceptor_loss	1.0000
9:124021095:CTAG:C	acceptor_loss	1.0000
9:124021097:A:AG	acceptor_gain	1.0000
9:124021097:A:T	acceptor_loss	1.0000
9:124021097:AGC:A	acceptor_gain	1.0000
9:124021098:G:GC	acceptor_gain	1.0000
9:124021098:GC:G	acceptor_gain	1.0000
9:124021098:GCG:G	acceptor_gain	1.0000
9:124021098:GCGC:G	acceptor_gain	1.0000
9:124021098:GCGCT:G	acceptor_gain	1.0000
9:124032417:CAG:C	acceptor_loss	1.0000
9:124032418:A:AT	acceptor_loss	1.0000

AlphaMissense

2666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:124013997:T:A	C53S	1.000
9:124013997:T:C	C53R	1.000
9:124013997:T:G	C53G	1.000
9:124013998:G:A	C53Y	1.000
9:124013998:G:C	C53S	1.000
9:124013998:G:T	C53F	1.000
9:124013999:C:G	C53W	1.000
9:124014004:G:A	G55D	1.000
9:124014006:T:A	C56S	1.000
9:124014006:T:C	C56R	1.000
9:124014007:G:A	C56Y	1.000
9:124014007:G:C	C56S	1.000
9:124014007:G:T	C56F	1.000
9:124014008:C:G	C56W	1.000
9:124014019:T:A	I60N	1.000
9:124014019:T:C	I60T	1.000
9:124014019:T:G	I60S	1.000
9:124014030:T:G	Y64D	1.000
9:124014033:T:G	Y65D	1.000
9:124014037:T:A	L66Q	1.000
9:124014037:T:C	L66P	1.000
9:124014040:T:C	L67P	1.000
9:124014042:G:C	A68P	1.000
9:124014043:C:A	A68E	1.000
9:124014057:T:A	W73R	1.000
9:124014057:T:C	W73R	1.000
9:124014058:G:C	W73S	1.000
9:124014058:G:T	W73L	1.000
9:124014059:G:C	W73C	1.000
9:124014059:G:T	W73C	1.000

dbSNP variants (sampled 300 via entrez): RS1000136269 (9:124030622 CTTTTCTTTT>C), RS1000414233 (9:124018974 A>G), RS1000507258 (9:124026197 G>A,C,T), RS1000617319 (9:124030830 A>C), RS1000707798 (9:124019839 C>A), RS1000726717 (9:124030490 C>A,G,T), RS1000738283 (9:124020186 A>G), RS1000868304 (9:124013474 G>A), RS1000956510 (9:124025027 C>T), RS1000995316 (9:124019246 C>T), RS1001108708 (9:124025214 G>A), RS1001381498 (9:124013098 G>T), RS1001382386 (9:124017482 C>A,G,T), RS1001401446 (9:124012456 C>G,T), RS1001401897 (9:124033635 C>A,T)

Disease associations

OMIM: gene MIM:603759 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	AD

Mondo (2): neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002137_7	Waist circumference	2.000000e-08
GCST002681_7	Post-traumatic stress disorder	9.000000e-07
GCST002927_8	Mercury levels	7.000000e-06
GCST005411_9	Thrombin-activatable fibrinolysis inhibitor activation peptide	4.000000e-07
GCST005839_1	Depression	3.000000e-08
GCST006075_10	Hair color	8.000000e-92
GCST006988_151	Blond vs. brown/black hair color	3.000000e-64
GCST006988_161	Blond vs. brown/black hair color	3.000000e-78
GCST006988_40	Blond vs. brown/black hair color	1.000000e-20
GCST007100_1	Asthma exacerbations in inhaled corticosteroid treatment	3.000000e-06
GCST007100_8	Asthma exacerbations in inhaled corticosteroid treatment	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003924	hair color
EFO:0007614	asthma exacerbation measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression, affects expression	7
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cisplatin	affects expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
bisphenol A	affects cotreatment, decreases methylation	1
arsenite	increases methylation	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mercuric bromide	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	increases expression	1
Resveratrol	increases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A3V0	SEES3-1V human LHX2, clone1	Embryonic stem cell	Male
CVCL_A3V1	SEES3-1V human LHX2, clone2	Embryonic stem cell	Male
CVCL_A3V2	SEES3-1V human LHX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism