GeneBe

LHX4

protein-coding

LIM homeobox 4, the group of LIM class homeoboxes

Gene summary

This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4. [provided by RefSeq, Dec 2010]

MANE transcript

NM_033343.4

Inheritance

AD

ClinVar variants

P:13U:132B:55

Top phenotype

Pituitary hormone deficiency, combined, 4

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr1:180,230,264-180,278,984

External References & Databases

Ensembl (ENSG00000121454)NCBI Gene (89884)OMIM (602146)HGNC:21734GenCCUniProt (Q969G2)AlphaFoldClinVar (LHX4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~48.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined pituitary hormone deficiencies, genetic formSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013099

Submitter: Orphanet

short stature-pituitary and cerebellar defects-small sella turcica syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009880

Submitter: Orphanet

short stature-pituitary and cerebellar defects-small sella turcica syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009880

Submitter: Labcorp Genetics (formerly Invitae)

short stature-pituitary and cerebellar defects-small sella turcica syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009880

Submitter: G2P

short stature-pituitary and cerebellar defects-small sella turcica syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009880

Submitter: Ambry Genetics

short stature-pituitary and cerebellar defects-small sella turcica syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009880

Submitter: PanelApp Australia

pituitary stalk interruption syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019828

Submitter: Orphanet

hypothyroidism due to deficient transcription factors involved in pituitary development or functionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016411

Submitter: Orphanet

Clinical Genomic Database (CGD)

Pituitary hormone deficiency, combined, 4AD

Manifestation: Endocrine; Musculoskeletal; Neurologic; Pulmonary

Intervention: Endocrine

Rationale: Individuals can prevent neonatally with severe manifestations due to endocrine anomalies such as hypoglycemia; Respiratory distress has also been described at presentation; Other corrections of endocrine anomalies, such as growth hormone deficiency treatment, can be beneficial

Refs: 11567216; 17527005; 18073311; 19856252; 20534763; 22232309; 23029363; 23761422Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LHX4 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 99
Inborn genetic diseasesTotal: 67
Short stature-pituitary and cerebellar defects-small sella turcica syndromeTotal: 54
not specifiedTotal: 51
LHX4-related disorderTotal: 19
Pituitary hormone deficiency, combined, 1Total: 2
Incidental DiscoveryTotal: 1
Combined pituitary hormone deficiencies, genetic formTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033343.4. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
38
clinvar
2
clinvar
 42
missense
3
clinvar
1
clinvar
124
clinvar
13
clinvar
1
clinvar
 142
nonsense
2
clinvar
1
clinvar
 3
start loss
1
clinvar
1
clinvar
 2
frameshift
3
clinvar
1
clinvar
2
clinvar
 6
splice donor/acceptor (+/-2bp)
2
clinvar
1
clinvar
2
clinvar
 5
Total85132523200

Highest pathogenic variant AF is 0.0000030976785

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_033343.4RefSeqNP_203129.16MANE Select
ENST00000263726.4EnsemblENSP00000263726.26MANE Select
ENST00000561113.1EnsemblENSP00000452783.13Standard
ENST00000930099.1EnsemblENSP00000600158.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Developmental Biology
  • Regulation of expression of SLITs and ROBOs
  • Signaling by ROBO receptors
  • Axon guidance

Biological Process

  • placenta development
  • motor neuron axon guidance
  • animal organ morphogenesis
  • medial motor column neuron differentiation
  • negative regulation of apoptotic process

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • protein binding
  • methyl-CpG binding
  • sequence-specific DNA binding

Cellular Component

  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000263726
Coding exons
6
Length
49960
Individuals with no LoFs
125734
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125748
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6702052340.8770.00001432584
Missense (PolyPhen)7688.80.85585992
Synonymous-0.47910094.11.060.00000610749
Loss of Function2.51617.30.3488.53e-7193

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000260.000026rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA (PubMed:28473536). {ECO:0000250, ECO:0000269|PubMed:28473536}.;
Disease
DISEASE: Pituitary hormone deficiency, combined, 4 (CPHD4) [MIM:262700]: Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD4 is characterized by complete or partial deficiencies of growth hormone, thyroid- stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. Clinical features include short stature, cerebellar defects, and small sella turcica. {ECO:0000269|PubMed:17527005, ECO:0000269|PubMed:18073311}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving LHX4 may be a cause of acute lymphoblastic leukemia. Translocation t(1;14)(q25;q32) with IGHG1. {ECO:0000269|PubMed:11567216}.;

Recessive Scores

pRec
0.204

Intolerance Scores

LoFtool
0.155
RVIS EVS
-0.45
RVIS percentile EVS
24.33

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.945

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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