IRX5

protein-coding

iroquois homeobox 5, the group of TALE class homeoboxes and pseudogenes

Gene summary

This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

MANE transcript

NM_005853.6

Inheritance

AR, AD

ClinVar variants

P:4U:93B:42

Top phenotype

Hamamy syndrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr16:54,930,865-54,934,485

External References & Databases

Ensembl (ENSG00000176842)

Transcript & Mutation Effects

hg38 • Region Span ~3.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

craniofacial dysplasia - osteopenia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012634

Submitter: G2P

cone dystrophyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0000455

Submitter: PanelApp Australia

craniofacial dysplasia - osteopenia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012634

Submitter: PanelApp Australia

craniofacial dysplasia - osteopenia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012634

Submitter: Orphanet

craniofacial dysplasia - osteopenia syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012634

Submitter: ClinGen

*IRX5* was first reported in relation to *IRX5*-related craniofacial dysostosis with osteopenia, intellectual disability and dental anomalies in 2012 by Bonnard et al. (PMID: 22581230). This condition, first described by Hamamy et al., 2007 (PMID: 17230486), includes features such as cranial anomalies (like brachycephaly); facial anomalies (including abnormal philtrum, bulging midface, broad nasal bridge; and extreme ocular hypertelorism); cleft palate/dental anomalies; hearing loss; vision issues (like progressive myopia); cardiac features (such as patent ductus arteriosus and intraventricular conduction delay); skeletal/digital features (like syndactyly, clinodactyly, hip dysplasia, and long bone fractures); genital features (gonadal issues, hydrocele, cryptorchidism); and developmental delay. 3 variants (missense) that have been reported in at least 4 probands in 3 publications (PMIDs: 22581230, 30729910, 34899143) are included in this curation. Additional genetic evidence (PMIDs: 28940097, 38318288) has been evaluated but not scored due to high allele frequencies, a different inheritance pattern, and/or variants in other associated genes. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse and xenopus models, rescue evidence, biochemical functional data, and interaction evidence; PMIDs: 22581230, 32662900). Biochemical functional evidence shows that IRX5 is key in bone development. Model organism evidence shows genital anomalies, bone issues (like reduced bone density), and deficient cranial neural crest cell migration in mutants. Deficient cranial neural crest migration in IRX5 morphants could be rescued with wild-type IRX5. Interaction evidence shows that IRX5 and TRPS1 exhibit co-immunoprecipitation amid craniofacial development. The maximum score for experimental evidence (6 pts.) has been reached. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting data 7/21/2025 (SOP Version 11).

craniofacial dysplasia - osteopenia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012634

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hamamy syndromeAR

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17230486; 22581230; 34899143

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IRX5 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 88

not providedTotal: 42

Craniofacial dysplasia - osteopenia syndromeTotal: 11

IRX5-related disorderTotal: 11

not specifiedTotal: 6

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005853.6. 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				35 clinvar	2 clinvar	37
missense	3 clinvar		92 clinvar	4 clinvar	1 clinvar	100
nonsense						0
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	4	0	93	39	3	139

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005853.6	RefSeq	NP_005844.4	3	MANE Select
ENST00000394636.9	Ensembl	ENSP00000378132.4	3	MANE Select
NM_001252197.1	RefSeq	NP_001239126.1	3	Standard
ENST00000320990.9	Ensembl	ENSP00000316250.5	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FTO Obesity Variant Mechanism
Preimplantation Embryo

Biological Process

regulation of heart rate
regulation of transcription by RNA polymerase II
visual perception
gonad development
neuron maturation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
vitamin D binding
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394636
Coding exons: 3
Length: 3624
Individuals with no LoFs: 125288
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125293
p: 0.0000200

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.831	232	270	0.858	0.0000129	3015
Missense (PolyPhen)		38	67.619	0.56197		741
Synonymous	-1.42	149	129	1.16	0.00000657	1057
Loss of Function	3.44	1	15.7	0.0636	7.29e-7	179

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000055	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene. Required for retinal cone bipolar cell differentiation. May regulate contrast adaptation in the retina and control specific aspects of visual function in circuits of the mammalian retina (By similarity). Could be involved in the regulation of both the cell cycle and apoptosis in prostate cancer cells. Involved in craniofacial and gonadal development. Modulates the migration of progenitor cell populations in branchial arches and gonads by repressing CXCL12. {ECO:0000250, ECO:0000269|PubMed:22581230}.;
Disease: DISEASE: Hamamy syndrome (HMMS) [MIM:611174]: A syndrome characterized by severe hypertelorism, upslanting palpebral fissures, brachycephaly, abnormal ears, sloping shoulders, enamel hypoplasia, and osteopenia with repeated fractures. Additional features include myopia, mild to moderate sensorineural hearing loss, gonadal anomalies and borderline intelligence. {ECO:0000269|PubMed:22581230}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.508

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium