GeneBe

HESX1

protein-coding

HESX homeobox 1, the group of PRD class homeoboxes and pseudogenes

Gene summary

This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003865.3

Inheritance

AD, AR

ClinVar variants

P:29U:74B:24

Top phenotype

Pituitary hormone deficiency, combined; Septooptic dysplasia

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr3:57,197,838-57,227,606

External References & Databases

Ensembl (ENSG00000163666)NCBI Gene (8820)OMIM (601802)HGNC:4877GenCCUniProt (Q9UBX0)AlphaFoldClinVar (HESX1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~29.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

septooptic dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: Orphanet

pituitary stalk interruption syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019828

Submitter: Orphanet

combined pituitary hormone deficiencies, genetic formSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013099

Submitter: Orphanet

septooptic dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: Ambry Genetics

combined pituitary hormone deficiencies, genetic formSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013099

Submitter: G2P

septooptic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008428

Submitter: Labcorp Genetics (formerly Invitae)

septooptic dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: Labcorp Genetics (formerly Invitae)

septooptic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008428

Submitter: G2P

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

septooptic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008428

Submitter: PanelApp Australia

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

Inheritance Pattern: AD

Disease ID:MONDO:0016411

Submitter: Orphanet

septooptic dysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008428

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Pituitary hormone deficiency, combined; Septooptic dysplasiaAD/AR

Manifestation: Endocrine; Neurologic; Ophthalmologic

Intervention: Endocrine

Rationale: Some individuals may have life-threatening adrenal insufficiency as well as additional endocrine insufficiency, and early recognition and immediate and long-term treatment can be beneficial

Refs: 8696006; 9620767; 11136712; 14561704; 12519827; 16940453; 22145475Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HESX1 variants in ClinVar

14 Conditions Cataloged
Septo-optic dysplasia sequenceTotal: 90
GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIESTotal: 77
not providedTotal: 45
Inborn genetic diseasesTotal: 33
not specifiedTotal: 19
HESX1-related disorderTotal: 10
Pituitary hormone deficiency, combined, 1Total: 6
HESX1-Related DisordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003865.3. 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
1
clinvar
18
clinvar
 19
missense
2
clinvar
4
clinvar
69
clinvar
6
clinvar
 81
nonsense
4
clinvar
2
clinvar
1
clinvar
 7
start loss
1
clinvar
1
clinvar
 2
frameshift
7
clinvar
6
clinvar
2
clinvar
 15
splice donor/acceptor (+/-2bp)
1
clinvar
2
clinvar
 3
Total141574240127

Highest pathogenic variant AF is 0.00014448949

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003865.3RefSeqNP_003856.14MANE Select
ENST00000295934.8EnsemblENSP00000295934.34MANE Select
NM_001376058.1RefSeqNP_001362987.14Standard
NM_001376059.1RefSeqNP_001362988.14Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Ectoderm Differentiation

Biological Process

  • regulation of transcription by RNA polymerase II
  • brain development
  • pituitary gland development

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA binding
  • protein binding

Cellular Component

  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000295934
Coding exons
4
Length
28606
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125748
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1579994.71.050.000004911205
Missense (PolyPhen)2124.550.8554310
Synonymous0.6803136.20.8560.00000195339
Loss of Function1.0769.560.6284.94e-7124

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000500.00050rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland. Possible transcriptional repressor. Binds to the palindromic PIII sequence, 5'-AGCTTGAGTCTAATTGAATTAACTGTAC-3'. HESX1 and PROP1 bind as heterodimers on this palindromic site, and, in vitro, HESX1 can antagonize PROP1 activation. {ECO:0000250|UniProtKB:Q61658, ECO:0000269|PubMed:26781211}.;
Disease
DISEASE: Septooptic dysplasia (SOD) [MIM:182230]: A clinically heterogeneous disorder defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia with panhypopopituitarism, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:9620767}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Growth hormone deficiency with pituitary anomalies (GHDPA) [MIM:182230]: A disease characterized by low or absent growth hormone levels, in the presence of a hypoplastic anterior pituitary lobe and ectopic or absent posterior pituitary lobe. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:17148560}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pituitary hormone deficiency, combined, 5 (CPHD5) [MIM:182230]: Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD5 is characterized by complete or partial deficiencies of growth hormone, thyroid- stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. {ECO:0000269|PubMed:11136712, ECO:0000269|PubMed:14561704, ECO:0000269|PubMed:26781211}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.194

Intolerance Scores

LoFtool
0.470
RVIS EVS
0.19
RVIS percentile EVS
66.82

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.571

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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