TBX4

protein-coding

T-box transcription factor 4, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001321120.2

Inheritance

SD, AD, AR

ClinVar variants

P:82U:172B:66

Top phenotype

Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr17:61,452,404-61,485,110

External References & Databases

Ensembl (ENSG00000121075)

Transcript & Mutation Effects

hg38 • Region Span ~32.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive ameliaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0011054

Submitter: PanelApp Australia

coxopodopatellar syndromeSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007841

Submitter: PanelApp Australia

heritable pulmonary arterial hypertensionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017148

Submitter: Orphanet

coxopodopatellar syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007841

Submitter: Orphanet

coxopodopatellar syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007841

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive ameliaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011054

Submitter: G2P

autosomal recessive ameliaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011054

Submitter: Ambry Genetics

pulmonary arterial hypertensionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

T-Box transcription factor 4 (TBX4) is a part of the T-box gene family which plays an important role in the development of hind limb and pelvis. TBX4 is also expressed in lung mesenchyme during early embryogenesis and regulates lung branching morphogenesis. Mutations in TBX4 were first identified in small patella syndrome (SPS), which is characterized by small or no kneecaps and weak pelvic bones. Genetic evidence: TBX4 was first associated with pulmonary arterial hypertension (PAH) through identification of a 3.75 Mb microdeletion of 17q22q23.2 in a patient with multiple congenital anomalies and PAH (PMID: 21271665). However, the deletion region included 15 known genes, and therefore this case could not be scored. Subsequent publications identified intragenic TBX4 mutations in PAH. Two patients with insertions in TBX4 gene causing a premature stop codon were scored from PMID: 23592887. These patients had SPS and PAH phenotypes. Three nonsense mutations were scored from PMID: 27587546, and the patients had idiopathic or familial forms of PAH. Two nonsense mutations (one de novo) and one deletion were scored from PMID: 29631995, and the patients either had familial or idiopathic forms of PAH. These variants yielded a total score of 12 for genetic evidence. Two more recent studies PMID: 29650961 and PMID: 31727138 add a further 7 and 8 frameshift/stop-gain mutations respectively which were not scored, but indicate very strong replication over time. Experimental evidence: Expression of TBX4 and functional consequence of variants in the gene are not yet widely studied in relevance to PAH. PMID: 22876201 demonstrated strong expression of TBX4 in developing lung and trachea. PMID: 33385213 reported that in vitro knockdown of TBX4 resulted in decreased p-Smad1/5. Two patient-derived lymphoblast lines (one with a frameshift deletion and other with complete deletion of TBX4) also had significantly lower levels of p-Smad1/5 when compared to control cells. Smad phosphorylation is a key mediator of bone morphogenetic signaling, and is known to be attenuated in PAH, especially in cells with a BMPR2 mutation. Therefore, this study was scored for biochemical function, since the effect of reduced TBX4 levels on Smad phosphorylation is similar to that caused by haploinsufficiency for BMPR2, the most common cause of heritable PAH. Overall, the experimental evidence from both the studies yielded a score of 1. The total score including both genetic and experimental evidence was 13 and since there is replication over time, the evidence was finally classified as DEFINITIVE.

coxopodopatellar syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007841

Submitter: G2P

coxopodopatellar syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007841

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertensionAD

Manifestation: Cardiovascular; Genitourinary; Musculoskeletal; Neurologic; Pulmonary

Intervention: Cardiovascular; Pulmonary

Rationale: The condition can include pulmonary artery hypertension, and awareness may allow prompt diagnosis and management

Refs: 15106123; 23592887; 30413314; 31151956; 31761294

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX4 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 149

Inborn genetic diseasesTotal: 78

Coxopodopatellar syndromeTotal: 77

Pulmonary hypertension, primary, 1Total: 70

not specifiedTotal: 44

TBX4-related disorderTotal: 36

Pulmonary arterial hypertensionTotal: 8

Autosomal recessive ameliaTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001321120.2. 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			5 clinvar	40 clinvar	3 clinvar	48
missense	4 clinvar	9 clinvar	151 clinvar	19 clinvar	4 clinvar	187
nonsense	11 clinvar	13 clinvar	6 clinvar			30
start loss		1 clinvar				1
frameshift	11 clinvar	22 clinvar	9 clinvar			42
splice donor/acceptor (+/-2bp)	4 clinvar	7 clinvar	1 clinvar			12
Total	30	52	172	59	7	320

Highest pathogenic variant AF is 0.0000935529

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001321120.2	RefSeq	NP_001308049.1	8	MANE Select
ENST00000644296.1	Ensembl	ENSP00000495986.1	8	MANE Select
NM_018488.3	RefSeq	NP_060958.2	8	Standard
ENST00000240335.1	Ensembl	ENSP00000240335.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbx4	Danio rerio	Structure: pelvic fin skeleton Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

tbx4

Danio rerio

Structure: pelvic fin skeleton

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

angiogenesis
morphogenesis of an epithelium
regulation of transcription, DNA-templated
regulation of transcription by RNA polymerase II
multicellular organism development

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240335
Coding exons: 8
Length: 32707
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.871	269	312	0.861	0.0000190	3537
Missense (PolyPhen)		95	134.4	0.70683		1579
Synonymous	-0.687	145	135	1.08	0.00000914	1103
Loss of Function	3.55	5	23.6	0.211	0.00000147	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transcriptional regulation of genes required for mesoderm differentiation. Probably plays a role in limb pattern formation.;
Disease: DISEASE: Ischiocoxopodopatellar syndrome (ICPPS) [MIM:147891]: An autosomal dominant bone disease characterized by patellar aplasia or hypoplasia and by anomalies of the pelvis and feet, including disrupted ossification of the ischia and inferior pubic rami. {ECO:0000269|PubMed:15106123}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.109
RVIS EVS: -0.58
RVIS percentile EVS: 18.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.790

Gene Damage Prediction

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