GeneBe

ALX4

protein-coding

ALX homeobox 4, the group of PRD class homeoboxes and pseudogenes

Gene summary

This gene encodes a paired-like homeodomain transcription factor expressed in the mesenchyme of developing bones, limbs, hair, teeth, and mammary tissue. Mutations in this gene cause parietal foramina 2 (PFM2); an autosomal dominant disease characterized by deficient ossification of the parietal bones. Mutations in this gene also cause a form of frontonasal dysplasia with alopecia and hypogonadism; suggesting a role for this gene in craniofacial development, mesenchymal-epithelial communication, and hair follicle development. Deletion of a segment of chromosome 11 containing this gene, del(11)(p11p12), causes Potocki-Shaffer syndrome (PSS); a syndrome characterized by craniofacial anomalies, cognitive disability, multiple exostoses, and genital abnormalities in males. In mouse, this gene has been shown to use dual translation initiation sites located 16 codons apart. [provided by RefSeq, Oct 2009]

Previous symbols:
  • PFM2

MANE transcript

NM_021926.4

Inheritance

AR, AD

ClinVar variants

P:29U:113B:47

Top phenotype

Parietal foramina 2; Frontonasal dysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr11:44,260,440-44,310,139

External References & Databases

Ensembl (ENSG00000052850)NCBI Gene (60529)OMIM (605420)HGNC:450GenCCUniProt (Q9H161)AlphaFoldClinVar (ALX4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~49.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

frontonasal dysplasia with alopecia and genital anomalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: G2P

parietal foramina 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012309

Submitter: Ambry Genetics

frontonasal dysplasia with alopecia and genital anomalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: ClinGen

ALX4 has been repeatedly described in association with autosomal recessive frontonasal dysplasia with alopecia and genital anomaly. Frontonasal dysplasia 1 is characterized by having a distinctive facial appearance with hypertelorism, broad nasal bridge, short nasal ridge, splayed nasal bones with bifid nasal tip, broad columella that attaches to the lip above the alae, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. At least 1 missense, 2 nonsense, 1 splice acceptor, and 1 deletion mutations have been reported in at least 5 probands from 4 publications (PMIDs: 19409524, 22106187, 29215096, 34098755) This gene disease association is also supported by experimental evidence including expression data and an animal model (PMID: 20534379). In summary, ALX4 is definitively associated with autosomal recessive Frontonasal dysplasia 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

parietal foramina 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012309

Submitter: Labcorp Genetics (formerly Invitae)

parietal foraminaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018953

Submitter: Orphanet

frontonasal dysplasia with alopecia and genital anomalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: Orphanet

frontonasal dysplasia with alopecia and genital anomalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: PanelApp Australia

craniosynostosis 5, susceptibility toSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014232

Submitter: PanelApp Australia

parietal foramina 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012309

Submitter: PanelApp Australia

frontonasal dysplasia with alopecia and genital anomalyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: Ambry Genetics

parietal foramina 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012309

Submitter: G2P

frontonasal dysplasia with alopecia and genital anomalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013268

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Parietal foramina 2; Frontonasal dysplasia 2AD/AR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic

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

Comments: Variants may contribute to nonsyndromic craniosynostosis

Refs: 11106354; 11137991; 16319823; 18541970; 19692347; 20301307; 22140057; 22829454; 23401352; 24668755; 24764194Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALX4 variants in ClinVar

12 Conditions Cataloged
not providedTotal: 86
Inborn genetic diseasesTotal: 76
Parietal foramina 2Total: 40
not specifiedTotal: 23
ALX4-related disorderTotal: 18
Frontonasal dysplasia with alopecia and genital anomalyTotal: 10
Craniosynostosis 5, susceptibility toTotal: 5
SIN3A-related intellectual disability syndrome due to a point mutationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021926.4. 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
7
clinvar
32
clinvar
3
clinvar
 42
missense
4
clinvar
1
clinvar
103
clinvar
10
clinvar
2
clinvar
 120
nonsense
5
clinvar
2
clinvar
1
clinvar
 8
start loss
1
clinvar
 1
frameshift
6
clinvar
11
clinvar
1
clinvar
 18
splice donor/acceptor (+/-2bp)
0
Total1514113425189

Highest pathogenic variant AF is 0.000014532329

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_021926.4RefSeqNP_068745.24MANE Select
ENST00000652299.1EnsemblENSP00000498217.14MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • skeletal system development
  • hair follicle development
  • muscle organ development
  • post-embryonic development
  • anterior/posterior pattern specification

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA binding
  • protein heterodimerization activity

Cellular Component

  • nucleus
  • transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000329255
Coding exons
4
Length
49723
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125748
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8212132490.8540.00001472615
Missense (PolyPhen)84104.530.803571030
Synonymous-1.531281081.190.00000653812
Loss of Function3.01417.60.2279.99e-7163

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00025rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000420.000035rare
South Asian0.0000650.000065rare
Other0.000350.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription factor involved in skull and limb development. Plays an essential role in craniofacial development, skin and hair follicle development. {ECO:0000269|PubMed:19692347}.;
Disease
DISEASE: Frontonasal dysplasia 2 (FND2) [MIM:613451]: The term frontonasal dysplasia describes an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. {ECO:0000269|PubMed:19692347}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Potocki-Shaffer syndrome (POSHS) [MIM:601224]: A syndrome characterized by foramina parietalia permagna, multiple exostoses, and craniofacial dysostosis and mental retardation in some cases. {ECO:0000305|PubMed:11017806, ECO:0000305|PubMed:11903336}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Craniosynostosis 5 (CRS5) [MIM:615529]: A primary abnormality of skull growth involving premature fusion of one or more cranial sutures. The growth velocity of the skull often cannot match that of the developing brain resulting in an abnormal head shape and, in some cases, increased intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability. {ECO:0000269|PubMed:22829454}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.216

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
0.946

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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