LHX2
protein-codingLIM homeobox 2, the group of LIM class homeoboxes
Gene summary
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. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*LHX2* encodes a LIM-homeodomain transcription factor that plays an important role in cortical development. *LHX2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2023 (Schmid et al., PMID: 37057675). Affected individuals present with global developmental delay, variable intellectual disability, behavioral anomalies including autism spectrum disorder, and microcephaly. Magnetic resonance imaging anomalies include dysgenesis of the corpus callosum, enlarged ventricles, and white matter lesions. Patients may present additional features such as ophthalmologic abnormalities (including macular degeneration and optic neuropathy), congenital heart defects, or subtle facial dysmorphisms. Ten variants (2 nonsense, 4 frameshift, and 4 missense) that have been reported in 10 probands in 1 publication (PMID: 37057675) are included in this curation. Functional studies showed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for a missense variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants (PMID: 37057675). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function (PMID: 37057675). This gene-disease relationship is also supported by studies of mouse models (PMIDs: 23454273, 24781987, 26371318). The deletion of *Lhx2* in mouse cortical progenitors by Nestin-cre leads to a dramatically smaller cortex, while inactivation of *Lhx2* in mouse cortical radial glia leads to complete absence of the corpus callosum. In summary, there is definitive evidence supporting the relationship between *LHX2* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 2, 2025. It was reevaluated on October 14, 2026 (SOP Version 12). As a result of this reevaluation, no new cases were found but the classification increased from Strong to Definitive because no contradictory evidence has emerged in the three years since the first publication.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LHX2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004789.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 9 | 1 | 11 | ||
| missense | 2 | 63 | 2 | 1 | 68 | |
| nonsense | 2 | 1 | 1 | 4 | ||
| start loss | 0 | |||||
| frameshift | 2 | 2 | 5 | 9 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 6 | 3 | 70 | 11 | 2 | 92 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004780.3 | 5 | MANE Select | |
| Ensembl | ENSP00000362717.4 | 5 | MANE Select | |
| Ensembl | ENSP00000394978.1 | 5 | Standard | |
| Ensembl | ENSP00000476200.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lhx2b | Danio rerio | Structure: retinal ganglion cell Quality: misrouted abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neural Crest Differentiation
- Developmental Biology
- Regulation of expression of SLITs and ROBOs
- Signaling by ROBO receptors
- Axon guidance
Biological Process
- neural tube closure
- hair follicle development
- axon guidance
- mesoderm development
- dorsal/ventral pattern formation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
- metal ion binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373615
- Coding exons
- 5
- Length
- 31632
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.27 | 143 | 243 | 0.589 | 0.0000126 | 2638 |
| Missense (PolyPhen) | 47 | 102.86 | 0.45692 | 1060 | ||
| Synonymous | -1.17 | 121 | 106 | 1.14 | 0.00000563 | 818 |
| Loss of Function | 3.39 | 0 | 13.4 | 0.00 | 6.23e-7 | 161 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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 (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.238
Intolerance Scores
- RVIS EVS
- -0.12
- RVIS percentile EVS
- 44.89
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.926