Vertebral Anomalies And Variable Endocrine And T-cell Dysfunction

Mendelian MONDO:0032607 Pathograph 21 Show in embeddings browser Disorders of Pharyngeal Apparatus Development Vertebral Segmentation Disorders

Vertebral anomalies and variable endocrine and T-cell dysfunction (VETD; OMIM 618223) is an ultra-rare autosomal dominant multisystem developmental disorder caused by heterozygous partial loss-of-function missense variants in TBX2, a T-box transcriptional repressor. It was defined from four individuals (a three-member family carrying p.Arg20Gln and an unrelated person with de novo p.Arg305His) whose findings overlap the 22q11.2 deletion (DiGeorge) spectrum: vertebral segmentation and fusion defects with scoliosis and kyphosis, craniofacial dysmorphism with cleft or high-arched palate, conotruncal and septal heart defects, thymic aplasia with immune deficiency, and variable endocrine dysfunction (hypoparathyroidism, autoimmune thyroiditis, growth hormone deficiency), with variable neurodevelopmental involvement. Mouse genetics place Tbx2 upstream of Tbx1 in pharyngeal endoderm and require it for outflow-tract, atrioventricular-canal and palatal-shelf development, which may account for the DiGeorge-like pattern. How TBX2 deficiency produces the vertebral defects is not established.

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1
Inheritance
6
Pathophys.
28
Phenotypes
2
Gaps
21
Pathograph
1
Genes
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous TBX2 variants segregate in an autosomal dominant manner (p.Arg20Gln in three affected relatives) or arise de novo (p.Arg305His).
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29726930 SUPPORT PRIMARY RESULT Human Clinical
"The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation."
Establishes autosomal dominant transmission and de novo occurrence of heterozygous TBX2 variants in the defining cohort.
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Discussions and Knowledge Gaps

2
Patients carry one partial loss-of-function TBX2 allele, yet mice heterozygous for a Tbx2 null allele appear normal. Is the human phenotype caused by a lower dosage threshold, a dominant effect of the missense proteins, or interaction with other loci such as TBX3 or TBX1?
HUMAN MODEL MISMATCH OPEN vetd_tbx2_dosage_mouse_mismatch
Attached to
pathophysiology#TBX2 Partial Loss of Function animal_models#Mouse
The proposed mechanism is reduced TBX2 dosage, but the only mouse genotypes that show the cardiac, palatal and pharyngeal defects are the homozygous null or compound Tbx2/Tbx3 or Tbx1/Tbx2 genotypes.
How does reduced TBX2 dosage cause vertebral fusion and hemivertebrae? No model has linked Tbx2 to somite segmentation or vertebral body formation.
KNOWLEDGE GAP OPEN vetd_vertebral_mechanism_gap
Attached to
pathophysiology#Abnormal Vertebral Segmentation
Vertebral anomalies name the disorder, but the pathograph node for them has no mechanistic upstream support beyond the genotype-phenotype association in four individuals.
⚙

Pathophysiology

6
TBX2 Partial Loss of Function
Heterozygous missense variants p.Arg20Gln (N-terminal) and p.Arg305His (near the T-box) reduce TBX2 protein levels and its transcriptional repressor activity, and behave as partial loss-of-function (hypomorphic) alleles in Drosophila heterologous expression assays. The disorder is therefore attributed to reduced TBX2 dosage during embryonic development.
TBX2 hgnc:11597 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TBX2 (hgnc:11597). hgnc:11597 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
DNA-binding transcription repressor activity, RNA polymerase II-specific GO:0001227 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227). GO:0001227 is a molecular function from the Gene Ontology.
Downstream
Impaired Pharyngeal Apparatus Development
Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis
Impaired Palatal Shelf Outgrowth
Abnormal Vertebral Segmentation
Show evidence (2 references)
PMID:29726930 SUPPORT PRIMARY RESULT In Vitro
"In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2."
Cell-based assays show both patient variants reduce TBX2 repressor activity and protein abundance.
PMID:29726930 SUPPORT PRIMARY RESULT Model Organism
"Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles."
In vivo Drosophila assays classify both variants as hypomorphic (partial loss-of-function) alleles.
Impaired Pharyngeal Apparatus Development
In the mouse, Tbx2 and Tbx3 act redundantly upstream of Tbx1 and hedgehog ligand expression in pharyngeal endoderm, and loss of two of the three genes produces severe pharyngeal hypoplasia. The pharyngeal pouches give rise to the thymus and parathyroid glands, so reduced TBX2 dosage is proposed to produce the DiGeorge-like thymic and parathyroid deficits seen in patients. That the human thymic aplasia arises this way is an inference from the mouse network, not a direct observation.
pharyngeal system development GO:0060037 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pharyngeal system development (GO:0060037). GO:0060037 is a biological process from the Gene Ontology.
Downstream
Impaired Thymus Development
Hypoparathyroidism
Show evidence (2 references)
PMID:22116936 SUPPORT Model Organism
"whereas Tbx2 and Tbx3 function redundantly upstream of Tbx1 and Hh ligand expression in pharyngeal endoderm"
Places Tbx2 upstream of Tbx1, the major 22q11.2 deletion gene, in pharyngeal endoderm.
PMID:22116936 SUPPORT INDIRECT Model Organism
"loss of two of the three genes results in severe pharyngeal hypoplasia and heart tube extension defects"
Compound loss of Tbx2 with Tbx1 or Tbx3 causes pharyngeal hypoplasia in mice; applying this to human TBX2 heterozygosity is an inference step.
Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis
Tbx2 is expressed in non-chamber myocardium of the outflow tract and atrioventricular canal, where it represses chamber differentiation. Tbx2-null mice have atrioventricular canal patterning defects and defective outflow-tract septation, and Tbx2/Tbx3 compound mutants fail to form atrioventricular cushions, the precursors of valves and septa. These requirements match the conotruncal (double outlet right ventricle), septal and valvular defects reported in patients. Heterozygous null mice appear normal, so the patient defects imply that the human missense alleles fall below a dosage threshold the mouse heterozygote does not reach, or interact with other loci.
outflow tract septum morphogenesis GO:0003148 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal outflow tract septum morphogenesis (GO:0003148). GO:0003148 is a biological process from the Gene Ontology. atrioventricular valve morphogenesis GO:0003181 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal atrioventricular valve morphogenesis (GO:0003181). GO:0003181 is a biological process from the Gene Ontology. pulmonary valve morphogenesis GO:0003184 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal pulmonary valve morphogenesis (GO:0003184). GO:0003184 is a biological process from the Gene Ontology.
Animal models
Tbx2 null mouse Mouse partially recapitulates Reproduces the cardiac developmental defects seen in patients, but only in the homozygous null.
Downstream
Conotruncal Heart Defects
Atrial septal defect
Pulmonic stenosis
Show evidence (2 references)
PMID:15459098 SUPPORT Model Organism
"Morphological defects are observed in development of the atrioventricular canal and septation of the outflow tract."
Tbx2-null embryos show atrioventricular canal and outflow-tract septation defects, the cardiac structures affected in patients.
PMID:22130515 SUPPORT Model Organism
"mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa"
Shows Tbx2 dosage, together with Tbx3, is required for the cushions that form cardiac valves and septa.
Impaired Palatal Shelf Outgrowth
Tbx2 is expressed in palatal shelf mesenchyme. Tbx2-null mice and Tbx2/Tbx3 double heterozygotes have cleft palate because the palatal shelves form but are small, grow slowly and fail to meet, with increased proliferation, apoptosis and Bmp4 and Cyclin D1 expression in the shelves.
secondary palate development GO:0062009 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased secondary palate development (GO:0062009). GO:0062009 is a biological process from the Gene Ontology.
Downstream
Cleft palate
High palate
Show evidence (2 references)
PMID:19769959 SUPPORT Model Organism
"Mice homozygous mutant for Tbx2 and mice double heterozygous for Tbx2 and Tbx3 exhibit a cleft palate phenotype arguing for an important contribution of Tbx2 and Tbx3 to palatogenesis."
Establishes that reduced Tbx2 dosage causes cleft palate in mice.
PMID:19769959 SUPPORT Model Organism
"In Tbx2-deficient embryos, the bilateral primordial palatal shelves form but are smaller and retarded in the outgrowth process. They do not make contact but retain the potential to fuse."
Identifies the step at which Tbx2 deficiency disrupts palatogenesis.
Abnormal Vertebral Segmentation
Patients have congenital vertebral segmentation and fusion defects (Klippel-Feil anomaly, thoracic fusions, hemivertebrae, rib fusions) with secondary scoliosis and kyphosis. TBX2 is expressed in developing bone and cartilage, but no model has shown how reduced TBX2 dosage disrupts somite segmentation or vertebral formation. This node records the human observation; its upstream link to TBX2 rests only on the genotype-phenotype association.
embryonic skeletal system morphogenesis GO:0048704 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic skeletal system morphogenesis (GO:0048704). GO:0048704 is a biological process from the Gene Ontology.
Downstream
Vertebral fusion
Hemivertebrae
Rib fusion
Scoliosis
Kyphosis
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"The other three individuals harbored a variant p.Arg20Gln and similarly had multi-organ defects, facial dysmorphisms and cleft palate, Klippel–Feil vertebral anomalies and congenital absence of the thymus"
Summarizes the vertebral segmentation (Klippel-Feil) anomalies in the p.Arg20Gln family from the defining report.
Impaired Thymus Development
The thymus fails to form in the p.Arg20Gln family. Because the thymus is the site of T-cell maturation, its absence is the presumed basis of the immune deficiency named in the disorder. T-cell counts are not reported in the cited abstracts.
thymus development GO:0048538 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thymus development (GO:0048538). GO:0048538 is a biological process from the Gene Ontology.
Downstream
Aplasia of the thymus
Immunodeficiency
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel–Feil vertebral anomalies and congenital absence of the thymus"
Reports congenital thymic absence in the p.Arg20Gln family.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Vertebral Anomalies And Variable Endocrine And T-cell Dysfunction Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

28
Cardiovascular 5
Conotruncal Heart Defects Double outlet right ventricle HP:0001719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Double outlet right ventricle (HP:0001719). HP:0001719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Double outlet right ventricle, valvular pulmonic stenosis"
The comparison table lists double outlet right ventricle in the p.Arg305His patient.
Pulmonic stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Valvular pulmonic stenosis, annotated with Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Double outlet right ventricle, valvular pulmonic stenosis"
The comparison table lists valvular pulmonic stenosis in the p.Arg305His patient.
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Atrial septal defect, patent ductus arteriosus"
The comparison table lists atrial septal defect in the p.Arg20Gln family.
Patent ductus arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Atrial septal defect, patent ductus arteriosus"
The comparison table lists patent ductus arteriosus in the p.Arg20Gln family.
Aplasia of the thymus HP:0005359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital absence of the thymus, annotated with Aplasia of the thymus (HP:0005359). HP:0005359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel–Feil vertebral anomalies and congenital absence of the thymus"
Reports congenital thymic absence in the p.Arg20Gln family.
Ear 2
Cupped ear HP:0000378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cupped ear (HP:0000378). HP:0000378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, depressed and broad nasal tip, cupped and low set ears"
The comparison table lists cupped ears in the p.Arg305His patient, as well as in the p.Arg20Gln family.
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, depressed and broad nasal tip, cupped and low set ears"
The comparison table lists low-set ears in the p.Arg305His patient.
Endocrine 3
Hypoparathyroidism HP:0000829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoparathyroidism (HP:0000829). HP:0000829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Endocrine | Autoimmune thyroiditis, hypoparathyroidism | Growth hormone deficiency"
The comparison table lists hypoparathyroidism in the p.Arg20Gln family.
Autoimmune thyroiditis Hashimoto thyroiditis HP:0000872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune thyroiditis, annotated with Hashimoto thyroiditis (HP:0000872). HP:0000872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Endocrine | Autoimmune thyroiditis, hypoparathyroidism | Growth hormone deficiency"
The comparison table lists autoimmune thyroiditis in the p.Arg20Gln family.
Growth hormone deficiency Decreased response to growth hormone stimulation test HP:0000824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth hormone deficiency, annotated with Decreased response to growth hormone stimulation test (HP:0000824). HP:0000824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"One of them had a de novo missense mutation p.Arg305His—just five amino acids downstream of ours—and consequently growth hormone deficiency"
Reports growth hormone deficiency in the p.Arg305His patient.
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
The comparison table lists hypertelorism in the p.Arg20Gln family.
Head and Neck 5
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"The other three individuals harbored a variant p.Arg20Gln and similarly had multi-organ defects, facial dysmorphisms and cleft palate"
Reports cleft palate in the p.Arg20Gln family.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High arched, narrow palate, annotated with High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"triangular facial shape with a high and narrow palate, depressed nasal bridge, epicanthal folds and cupped ears"
Reports a high, narrow palate in the p.Arg305His patient.
Triangular face HP:0000325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Triangular face (HP:0000325). HP:0000325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
The comparison table lists a triangular face in the p.Arg20Gln family; the p.Arg305His patient also had one.
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthal folds, annotated with Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
The comparison table lists epicanthal folds in the p.Arg20Gln family.
Depressed nasal bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
The comparison table lists a depressed nasal bridge in the p.Arg20Gln family.
Immune 1
Immunodeficiency HP:0002721 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Immune deficiency, annotated with Immunodeficiency (HP:0002721). HP:0002721 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29726930 SUPPORT PRIMARY RESULT Human Clinical
"We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments"
Immune deficiency is part of the core phenotype in the defining cohort.
Musculoskeletal 7
Vertebral fusion HP:0002948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral fusion (HP:0002948). HP:0002948 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"One of them had a de novo missense mutation p.Arg305His—just five amino acids downstream of ours—and consequently growth hormone deficiency, congenital fusions of thoracic spine and hemivertebrae, scoliosis and kyphosis"
Reports thoracic vertebral fusions in the de novo p.Arg305His patient.
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
The comparison table lists Klippel-Feil anomaly (congenital cervical vertebral fusion) in the p.Arg20Gln family.
Hemivertebrae HP:0002937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemivertebrae (HP:0002937). HP:0002937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"congenital fusions of thoracic spine and hemivertebrae, scoliosis and kyphosis"
Reports hemivertebrae in the p.Arg305His patient.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
The comparison table lists scoliosis in the p.Arg20Gln family; the p.Arg305His patient also had scoliosis.
Kyphosis HP:0002808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphosis (HP:0002808). HP:0002808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Fusions of thoracic spine, scoliosis and kyphosis"
The comparison table lists kyphosis in the p.Arg305His patient.
Rib fusion HP:0000902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rib fusion (HP:0000902). HP:0000902 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
The comparison table lists rib fusions in the p.Arg20Gln family.
Sprengel anomaly HP:0000912 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sprengel anomaly (HP:0000912). HP:0000912 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
The comparison table lists Sprengel deformities in the p.Arg20Gln family.
Camptodactyly HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
The comparison table lists camptodactyly in the p.Arg20Gln family.
Nervous System 3
Neonatal seizure HP:0032807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal seizures, annotated with Neonatal seizure (HP:0032807). HP:0032807 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Normal to autistic behaviors, neonatal seizures"
The comparison table lists neonatal seizures in the p.Arg20Gln family.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Normal to autistic behaviors, neonatal seizures"
The comparison table lists autistic behaviors, ranging to normal, in the p.Arg20Gln family.
Developmental impairment Neurodevelopmental abnormality HP:0012759 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental impairment, annotated with Neurodevelopmental abnormality (HP:0012759). HP:0012759 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29726930 SUPPORT PRIMARY RESULT Human Clinical
"endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome"
Developmental impairment is part of the phenotype spectrum in the defining cohort.
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Normal to autistic behaviors, neonatal seizures | Mild cognitive impairments"
The comparison table lists mild cognitive impairments in the p.Arg305His patient.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35311234 SUPPORT BACKGROUND Human Clinical
"Growth | Height 3rd to 36th percentile | Height 2nd percentile"
The comparison table gives height at the 2nd percentile for the p.Arg305His patient and 3rd to 36th percentile for the p.Arg20Gln family.
🧬

Genetic Associations

1
TBX2 (Heterozygous partial loss-of-function variants)
Gene: TBX2 hgnc:11597 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TBX2 (hgnc:11597). hgnc:11597 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:29726930 SUPPORT PRIMARY RESULT Human Clinical
"Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder."
The defining study proposes TBX2 as the causal gene. The claim is candidate-level and rests on four individuals, which is why the relationship carries no validity tier.
📊

Prevalence

1
Published literature worldwide
Cases In Literature Ultra Rare
The phenotype was defined from four individuals in two families. No population-based prevalence estimate exists.
Show evidence (1 reference)
PMID:29726930 SUPPORT PRIMARY RESULT Human Clinical
"We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants."
The defining report describes four affected individuals, placing the disorder in the ultra-rare, literature-case range.
🐁

Animal Models

1
Tbx2 null mouse
Homozygous Tbx2-null embryos have atrioventricular canal and outflow-tract septation defects and hindlimb digit anomalies; heterozygotes appear normal.
Species
Mouse
Genotype
Tbx2 targeted null allele
Publication
PMID:15459098
Pathograph links
Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis partially recapitulates fidelity: low observes: tissue Reproduces the cardiac developmental defects seen in patients, but only in the homozygous null.
Limitations: Patients are heterozygous for hypomorphic missense alleles, whereas mouse heterozygotes for a null allele appear normal, so the model shows that Tbx2 is required but not the human dosage threshold.
Divergences from the human mechanism
species mismatch qualifying
The cardiac phenotype appears only in homozygous null mice, while one hypomorphic allele causes disease in humans, so mouse and human differ in their sensitivity to Tbx2 dosage.
Show evidence (1 reference)
PMID:15459098 SUPPORT Model Organism
"Mice heterozygous for a Tbx2 null mutation appear normal but homozygous embryos reveal a crucial role for Tbx2 during cardiac development."
States both the cardiac requirement and the normal heterozygote, which limits the model's fidelity to the heterozygous human disorder.
{ }

Source YAML

click to show 
name: Vertebral Anomalies And Variable Endocrine And T-cell Dysfunction
synonyms:
- VETD
- TBX2-related multisystem developmental disorder
creation_date: '2026-10-15T15:10:30Z'
category: Mendelian
description: >-
  Vertebral anomalies and variable endocrine and T-cell dysfunction (VETD; OMIM
  618223) is an ultra-rare autosomal dominant multisystem developmental disorder
  caused by heterozygous partial loss-of-function missense variants in TBX2, a
  T-box transcriptional repressor. It was defined from four individuals (a
  three-member family carrying p.Arg20Gln and an unrelated person with de novo
  p.Arg305His) whose findings overlap the 22q11.2 deletion (DiGeorge) spectrum:
  vertebral segmentation and fusion defects with scoliosis and kyphosis,
  craniofacial dysmorphism with cleft or high-arched palate, conotruncal and
  septal heart defects, thymic aplasia with immune deficiency, and variable
  endocrine dysfunction (hypoparathyroidism, autoimmune thyroiditis, growth
  hormone deficiency), with variable neurodevelopmental involvement. Mouse
  genetics place Tbx2 upstream of Tbx1 in pharyngeal endoderm and require it for
  outflow-tract, atrioventricular-canal and palatal-shelf development, which
  may account for the DiGeorge-like pattern. How TBX2 deficiency produces the
  vertebral defects is not established.
disease_term:
  preferred_term: vertebral anomalies and variable endocrine and T-cell dysfunction
  term:
    id: MONDO:0032607
    label: vertebral anomalies and variable endocrine and T-cell dysfunction
parents:
- Disorders of Pharyngeal Apparatus Development
- Vertebral Segmentation Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous TBX2 variants segregate in an autosomal dominant manner
    (p.Arg20Gln in three affected relatives) or arise de novo (p.Arg305His).
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation."
    explanation: Establishes autosomal dominant transmission and de novo occurrence of heterozygous TBX2 variants in the defining cohort.
prevalence:
- population: Published literature worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The phenotype was defined from four individuals in two families. No
    population-based prevalence estimate exists.
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants."
    explanation: The defining report describes four affected individuals, placing the disorder in the ultra-rare, literature-case range.
pathophysiology:
- name: TBX2 Partial Loss of Function
  description: >-
    Heterozygous missense variants p.Arg20Gln (N-terminal) and p.Arg305His
    (near the T-box) reduce TBX2 protein levels and its transcriptional
    repressor activity, and behave as partial loss-of-function (hypomorphic)
    alleles in Drosophila heterologous expression assays. The disorder is
    therefore attributed to reduced TBX2 dosage during embryonic development.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TBX2
    term:
      id: hgnc:11597
      label: TBX2
  molecular_functions:
  - preferred_term: DNA-binding transcription repressor activity, RNA polymerase II-specific
    modifier: DECREASED
    term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase II-specific
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: IN_VITRO
    snippet: "In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2."
    explanation: Cell-based assays show both patient variants reduce TBX2 repressor activity and protein abundance.
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles."
    explanation: In vivo Drosophila assays classify both variants as hypomorphic (partial loss-of-function) alleles.
  downstream:
  - target: Impaired Pharyngeal Apparatus Development
    causal_link_type: DIRECT
  - target: Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis
    causal_link_type: DIRECT
  - target: Impaired Palatal Shelf Outgrowth
    causal_link_type: DIRECT
  - target: Abnormal Vertebral Segmentation
- name: Impaired Pharyngeal Apparatus Development
  description: >-
    In the mouse, Tbx2 and Tbx3 act redundantly upstream of Tbx1 and hedgehog
    ligand expression in pharyngeal endoderm, and loss of two of the three
    genes produces severe pharyngeal hypoplasia. The pharyngeal pouches give
    rise to the thymus and parathyroid glands, so reduced TBX2 dosage is
    proposed to produce the DiGeorge-like thymic and parathyroid deficits seen
    in patients. That the human thymic aplasia arises this way is an inference
    from the mouse network, not a direct observation.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: pharyngeal system development
    modifier: DECREASED
    term:
      id: GO:0060037
      label: pharyngeal system development
  evidence:
  - reference: PMID:22116936
    reference_title: Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "whereas Tbx2 and Tbx3 function redundantly upstream of Tbx1 and Hh ligand expression in pharyngeal endoderm"
    explanation: Places Tbx2 upstream of Tbx1, the major 22q11.2 deletion gene, in pharyngeal endoderm.
  - reference: PMID:22116936
    reference_title: Identification of a Tbx1/Tbx2/Tbx3 genetic pathway governing pharyngeal and arterial pole morphogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of two of the three genes results in severe pharyngeal hypoplasia and heart tube extension defects"
    explanation: Compound loss of Tbx2 with Tbx1 or Tbx3 causes pharyngeal hypoplasia in mice; applying this to human TBX2 heterozygosity is an inference step.
  downstream:
  - target: Impaired Thymus Development
  - target: Hypoparathyroidism
- name: Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis
  description: >-
    Tbx2 is expressed in non-chamber myocardium of the outflow tract and
    atrioventricular canal, where it represses chamber differentiation. Tbx2-null
    mice have atrioventricular canal patterning defects and defective
    outflow-tract septation, and Tbx2/Tbx3 compound mutants fail to form
    atrioventricular cushions, the precursors of valves and septa. These
    requirements match the conotruncal (double outlet right ventricle), septal
    and valvular defects reported in patients. Heterozygous null mice appear
    normal, so the patient defects imply that the human missense alleles fall
    below a dosage threshold the mouse heterozygote does not reach, or interact
    with other loci.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: outflow tract septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003148
      label: outflow tract septum morphogenesis
  - preferred_term: atrioventricular valve morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003181
      label: atrioventricular valve morphogenesis
  - preferred_term: pulmonary valve morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003184
      label: pulmonary valve morphogenesis
  evidence:
  - reference: PMID:15459098
    reference_title: Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Morphological defects are observed in development of the atrioventricular canal and septation of the outflow tract."
    explanation: Tbx2-null embryos show atrioventricular canal and outflow-tract septation defects, the cardiac structures affected in patients.
  - reference: PMID:22130515
    reference_title: Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant mice lacking 3 or 4 functional alleles of Tbx2 and Tbx3 failed to form atrioventricular cushions, precursors of the valves and septa"
    explanation: Shows Tbx2 dosage, together with Tbx3, is required for the cushions that form cardiac valves and septa.
  downstream:
  - target: Conotruncal Heart Defects
  - target: Atrial septal defect
  - target: Pulmonic stenosis
- name: Impaired Palatal Shelf Outgrowth
  description: >-
    Tbx2 is expressed in palatal shelf mesenchyme. Tbx2-null mice and
    Tbx2/Tbx3 double heterozygotes have cleft palate because the palatal
    shelves form but are small, grow slowly and fail to meet, with increased
    proliferation, apoptosis and Bmp4 and Cyclin D1 expression in the shelves.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: secondary palate development
    modifier: DECREASED
    term:
      id: GO:0062009
      label: secondary palate development
  evidence:
  - reference: PMID:19769959
    reference_title: Expression and requirement of T-box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice homozygous mutant for Tbx2 and mice double heterozygous for Tbx2 and Tbx3 exhibit a cleft palate phenotype arguing for an important contribution of Tbx2 and Tbx3 to palatogenesis."
    explanation: Establishes that reduced Tbx2 dosage causes cleft palate in mice.
  - reference: PMID:19769959
    reference_title: Expression and requirement of T-box transcription factors Tbx2 and Tbx3 during secondary palate development in the mouse.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Tbx2-deficient embryos, the bilateral primordial palatal shelves form but are smaller and retarded in the outgrowth process. They do not make contact but retain the potential to fuse."
    explanation: Identifies the step at which Tbx2 deficiency disrupts palatogenesis.
  downstream:
  - target: Cleft palate
  - target: High palate
- name: Abnormal Vertebral Segmentation
  description: >-
    Patients have congenital vertebral segmentation and fusion defects
    (Klippel-Feil anomaly, thoracic fusions, hemivertebrae, rib fusions) with
    secondary scoliosis and kyphosis. TBX2 is expressed in developing bone and
    cartilage, but no model has shown how reduced TBX2 dosage disrupts somite
    segmentation or vertebral formation. This node records the human
    observation; its upstream link to TBX2 rests only on the genotype-phenotype
    association.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: embryonic skeletal system morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048704
      label: embryonic skeletal system morphogenesis
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The other three individuals harbored a variant p.Arg20Gln and similarly had multi-organ defects, facial dysmorphisms and cleft palate, Klippel–Feil vertebral anomalies and congenital absence of the thymus"
    explanation: Summarizes the vertebral segmentation (Klippel-Feil) anomalies in the p.Arg20Gln family from the defining report.
  downstream:
  - target: Vertebral fusion
  - target: Hemivertebrae
  - target: Rib fusion
  - target: Scoliosis
  - target: Kyphosis
- name: Impaired Thymus Development
  description: >-
    The thymus fails to form in the p.Arg20Gln family. Because the thymus is
    the site of T-cell maturation, its absence is the presumed basis of the
    immune deficiency named in the disorder. T-cell counts are not reported in
    the cited abstracts.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: thymus development
    modifier: DECREASED
    term:
      id: GO:0048538
      label: thymus development
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel–Feil vertebral anomalies and congenital absence of the thymus"
    explanation: Reports congenital thymic absence in the p.Arg20Gln family.
  downstream:
  - target: Aplasia of the thymus
  - target: Immunodeficiency
phenotypes:
- category: Skeletal
  name: Vertebral fusion
  description: Congenital vertebral fusions, including Klippel-Feil anomaly and thoracic spine fusions.
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "One of them had a de novo missense mutation p.Arg305His—just five amino acids downstream of ours—and consequently growth hormone deficiency, congenital fusions of thoracic spine and hemivertebrae, scoliosis and kyphosis"
    explanation: Reports thoracic vertebral fusions in the de novo p.Arg305His patient.
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
    explanation: The comparison table lists Klippel-Feil anomaly (congenital cervical vertebral fusion) in the p.Arg20Gln family.
- category: Skeletal
  name: Hemivertebrae
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "congenital fusions of thoracic spine and hemivertebrae, scoliosis and kyphosis"
    explanation: Reports hemivertebrae in the p.Arg305His patient.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
    explanation: The comparison table lists scoliosis in the p.Arg20Gln family; the p.Arg305His patient also had scoliosis.
- category: Skeletal
  name: Kyphosis
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Fusions of thoracic spine, scoliosis and kyphosis"
    explanation: The comparison table lists kyphosis in the p.Arg305His patient.
- category: Skeletal
  name: Rib fusion
  phenotype_term:
    preferred_term: Rib fusion
    term:
      id: HP:0000902
      label: Rib fusion
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
    explanation: The comparison table lists rib fusions in the p.Arg20Gln family.
- category: Skeletal
  name: Sprengel anomaly
  phenotype_term:
    preferred_term: Sprengel anomaly
    term:
      id: HP:0000912
      label: Sprengel anomaly
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
    explanation: The comparison table lists Sprengel deformities in the p.Arg20Gln family.
- category: Skeletal
  name: Camptodactyly
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel-Feil anomaly, rib fusions, scoliosis, camptodactyly, Sprengel deformities"
    explanation: The comparison table lists camptodactyly in the p.Arg20Gln family.
- category: Growth
  name: Short stature
  description: >-
    Height at the 2nd percentile in the p.Arg305His patient, who also had
    growth hormone deficiency. The p.Arg20Gln family members were between the
    3rd and 36th percentiles, so short stature is not claimed for them.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Growth | Height 3rd to 36th percentile | Height 2nd percentile"
    explanation: The comparison table gives height at the 2nd percentile for the p.Arg305His patient and 3rd to 36th percentile for the p.Arg20Gln family.
- category: Craniofacial
  name: Cleft palate
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The other three individuals harbored a variant p.Arg20Gln and similarly had multi-organ defects, facial dysmorphisms and cleft palate"
    explanation: Reports cleft palate in the p.Arg20Gln family.
- category: Craniofacial
  name: High palate
  description: High, narrow palate in the p.Arg305His patient.
  phenotype_term:
    preferred_term: High arched, narrow palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "triangular facial shape with a high and narrow palate, depressed nasal bridge, epicanthal folds and cupped ears"
    explanation: Reports a high, narrow palate in the p.Arg305His patient.
- category: Craniofacial
  name: Triangular face
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
    explanation: The comparison table lists a triangular face in the p.Arg20Gln family; the p.Arg305His patient also had one.
- category: Craniofacial
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
    explanation: The comparison table lists hypertelorism in the p.Arg20Gln family.
- category: Craniofacial
  name: Epicanthus
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
    explanation: The comparison table lists epicanthal folds in the p.Arg20Gln family.
- category: Craniofacial
  name: Depressed nasal bridge
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, hypertelorism with epicanthal folds, depressed nasal bridge, cupped and low set ears"
    explanation: The comparison table lists a depressed nasal bridge in the p.Arg20Gln family.
- category: Craniofacial
  name: Cupped ear
  phenotype_term:
    preferred_term: Cupped ear
    term:
      id: HP:0000378
      label: Cupped ear
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, depressed and broad nasal tip, cupped and low set ears"
    explanation: The comparison table lists cupped ears in the p.Arg305His patient, as well as in the p.Arg20Gln family.
- category: Craniofacial
  name: Low-set ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Triangular face, depressed and broad nasal tip, cupped and low set ears"
    explanation: The comparison table lists low-set ears in the p.Arg305His patient.
- category: Cardiovascular
  name: Conotruncal Heart Defects
  description: Double outlet right ventricle in the p.Arg305His patient.
  phenotype_term:
    preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Double outlet right ventricle, valvular pulmonic stenosis"
    explanation: The comparison table lists double outlet right ventricle in the p.Arg305His patient.
- category: Cardiovascular
  name: Pulmonic stenosis
  phenotype_term:
    preferred_term: Valvular pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Double outlet right ventricle, valvular pulmonic stenosis"
    explanation: The comparison table lists valvular pulmonic stenosis in the p.Arg305His patient.
- category: Cardiovascular
  name: Atrial septal defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Atrial septal defect, patent ductus arteriosus"
    explanation: The comparison table lists atrial septal defect in the p.Arg20Gln family.
- category: Cardiovascular
  name: Patent ductus arteriosus
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Atrial septal defect, patent ductus arteriosus"
    explanation: The comparison table lists patent ductus arteriosus in the p.Arg20Gln family.
- category: Immunological
  name: Aplasia of the thymus
  phenotype_term:
    preferred_term: Congenital absence of the thymus
    term:
      id: HP:0005359
      label: Aplasia of the thymus
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Klippel–Feil vertebral anomalies and congenital absence of the thymus"
    explanation: Reports congenital thymic absence in the p.Arg20Gln family.
- category: Immunological
  name: Immunodeficiency
  description: >-
    Immune deficiency, attributed in the disease name to T-cell dysfunction.
    The cited abstracts do not report T-cell counts, so the broader
    immunodeficiency term is bound rather than a T-cell count term.
  phenotype_term:
    preferred_term: Immune deficiency
    term:
      id: HP:0002721
      label: Immunodeficiency
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments"
    explanation: Immune deficiency is part of the core phenotype in the defining cohort.
- category: Endocrine
  name: Hypoparathyroidism
  phenotype_term:
    preferred_term: Hypoparathyroidism
    term:
      id: HP:0000829
      label: Hypoparathyroidism
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Endocrine | Autoimmune thyroiditis, hypoparathyroidism | Growth hormone deficiency"
    explanation: The comparison table lists hypoparathyroidism in the p.Arg20Gln family.
- category: Endocrine
  name: Autoimmune thyroiditis
  phenotype_term:
    preferred_term: Autoimmune thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Endocrine | Autoimmune thyroiditis, hypoparathyroidism | Growth hormone deficiency"
    explanation: The comparison table lists autoimmune thyroiditis in the p.Arg20Gln family.
- category: Endocrine
  name: Growth hormone deficiency
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "One of them had a de novo missense mutation p.Arg305His—just five amino acids downstream of ours—and consequently growth hormone deficiency"
    explanation: Reports growth hormone deficiency in the p.Arg305His patient.
- category: Neurological
  name: Neonatal seizure
  phenotype_term:
    preferred_term: Neonatal seizures
    term:
      id: HP:0032807
      label: Neonatal seizure
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Normal to autistic behaviors, neonatal seizures"
    explanation: The comparison table lists neonatal seizures in the p.Arg20Gln family.
- category: Neurological
  name: Autistic behavior
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Normal to autistic behaviors, neonatal seizures"
    explanation: The comparison table lists autistic behaviors, ranging to normal, in the p.Arg20Gln family.
- category: Neurological
  name: Developmental impairment
  description: Variable developmental impairment, including mild cognitive impairment in the p.Arg305His patient.
  phenotype_term:
    preferred_term: Developmental impairment
    term:
      id: HP:0012759
      label: Neurodevelopmental abnormality
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome"
    explanation: Developmental impairment is part of the phenotype spectrum in the defining cohort.
  - reference: PMID:35311234
    reference_title: A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Normal to autistic behaviors, neonatal seizures | Mild cognitive impairments"
    explanation: The comparison table lists mild cognitive impairments in the p.Arg305His patient.
genetic:
- name: TBX2
  gene_term:
    preferred_term: TBX2
    term:
      id: hgnc:11597
      label: TBX2
  association: Heterozygous partial loss-of-function variants
  relationship_type: CAUSATIVE
  notes: >-
    Reported causal variants are p.Arg20Gln (inherited, three relatives) and
    p.Arg305His (de novo). No ClinGen gene-disease validity assertion exists
    for TBX2 and this disease, and the defining report calls TBX2 a candidate
    gene. CAUSATIVE records that TBX2 variants define this disease (OMIM
    618223), not a ClinGen Definitive or Strong validity tier. Other heterozygous TBX2 variants have been
    reported with different phenotypes that are not curated here: p.Thr300Met
    in an autosomal dominant osteochondrodysplasia with empty sella
    (PMID:35311234), a de novo p.Lys177* nonsense variant in severe
    chondrodysplasia with developmental delay (PMID:36733940), and frameshift
    variants in progressive sensorineural hearing loss with variable nystagmus
    (PMID:40962492).
  evidence:
  - reference: PMID:29726930
    reference_title: Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder."
    explanation: The defining study proposes TBX2 as the causal gene. The claim is candidate-level and rests on four individuals, which is why the relationship carries no validity tier.
animal_models:
- name: Tbx2 null mouse
  species: Mouse
  genotype: Tbx2 targeted null allele
  publication: PMID:15459098
  description: >-
    Homozygous Tbx2-null embryos have atrioventricular canal and outflow-tract
    septation defects and hindlimb digit anomalies; heterozygotes appear normal.
  modeled_mechanisms:
  - target: Abnormal Outflow Tract and Atrioventricular Canal Morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Reproduces the cardiac developmental defects seen in patients, but only in the homozygous null.
    limitations: >-
      Patients are heterozygous for hypomorphic missense alleles, whereas mouse
      heterozygotes for a null allele appear normal, so the model shows that
      Tbx2 is required but not the human dosage threshold.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The cardiac phenotype appears only in homozygous null mice, while one
        hypomorphic allele causes disease in humans, so mouse and human differ
        in their sensitivity to Tbx2 dosage.
    evidence:
    - reference: PMID:15459098
      reference_title: Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice heterozygous for a Tbx2 null mutation appear normal but homozygous embryos reveal a crucial role for Tbx2 during cardiac development."
      explanation: States both the cardiac requirement and the normal heterozygote, which limits the model's fidelity to the heterozygous human disorder.
discussions:
- discussion_id: vetd_tbx2_dosage_mouse_mismatch
  prompt: >-
    Patients carry one partial loss-of-function TBX2 allele, yet mice
    heterozygous for a Tbx2 null allele appear normal. Is the human phenotype
    caused by a lower dosage threshold, a dominant effect of the missense
    proteins, or interaction with other loci such as TBX3 or TBX1?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#TBX2 Partial Loss of Function
  - animal_models#Mouse
  rationale: >-
    The proposed mechanism is reduced TBX2 dosage, but the only mouse genotypes
    that show the cardiac, palatal and pharyngeal defects are the homozygous
    null or compound Tbx2/Tbx3 or Tbx1/Tbx2 genotypes.
- discussion_id: vetd_vertebral_mechanism_gap
  prompt: >-
    How does reduced TBX2 dosage cause vertebral fusion and hemivertebrae? No
    model has linked Tbx2 to somite segmentation or vertebral body formation.
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Abnormal Vertebral Segmentation
  rationale: >-
    Vertebral anomalies name the disorder, but the pathograph node for them has
    no mechanistic upstream support beyond the genotype-phenotype association
    in four individuals.
notes: >-
  No GeneReviews chapter covers this disorder. Most clinical features are
  quoted from the comparison table and discussion of PMID:35311234, a full-text
  article that summarizes the patients of the defining report (PMID:29726930),
  because the defining report is cached as an abstract only. No treatment is
  recorded because none could be cited. The deep-research report states,
  citing an Undiagnosed Diseases Network web page rather than a publication,
  that the p.Arg20Gln proband had complete athymia treated by thymus
  transplantation. That claim was not encoded, and a citable source for it
  is still needed.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

No GeneReviews chapter covers this disorder. Most clinical features are quoted from the comparison table and discussion of PMID:35311234, a full-text article that summarizes the patients of the defining report (PMID:29726930), because the defining report is cached as an abstract only. No treatment is recorded because none could be cited. The deep-research report states, citing an Undiagnosed Diseases Network web page rather than a publication, that the p.Arg20Gln proband had complete athymia treated by thymus transplantation. That claim was not encoded, and a citable source for it is still needed.

Create: Vertebral_Anomalies_And_Variable_Endocrine_And_T-cell_Dysfunction · 2026-10-15T15:22:19Z · View source

Created a new entry for VETD (MONDO:0032607, TBX2), claim issue #14341. Deep research: falcon was requested by default but failed twice with an Edison authentication error (503), including with --fallback, so the claude_code provider was run instead (research/Vertebral_Anomalies_And_Variable_Endocrine_And_T-cell_Dysfunction-deep-research-claude_code.md; 17/17 references resolved). Its thymus-transplant and severe T-cell deficiency details come from a UDN web page with no PMID and were not encoded. Phenotypes are quoted from PMID:35311234 (full text, comparison table summarizing the defining cohort, quote_role BACKGROUND) and PMID:29726930 (abstract). Mechanism chain from mouse Tbx2 studies (PMIDs 22116936, 15459098, 22130515, 19769959). Allelic TBX2 phenotypes (osteochondrodysplasia with empty sella, chondrodysplasia, hearing loss) are noted but not curated. No GeneReviews chapter (check-genereviews --online: NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets (41/41), check-entity-refs, check-causal-targets, check-snippet-length and the other offline gates. A fresh-context review before the PR led to these changes: short stature added for the p.Arg305His patient only; the thymus node renamed to Impaired Thymus Development at TISSUE scale, with the T-cell binding removed; the immunodeficiency preferred_term no longer claims T-cell specificity; GO:0003184 pulmonary valve morphogenesis added; quote_role PRIMARY_RESULT set on PMID:29726930 items; Klippel-Feil and mild cognitive impairment snippets added; a note added that CAUSATIVE records the defining gene, not a validity tier. Not taken: Narrow palate as a second binding, and proposed experiments for the mouse-mismatch discussion, since no specific experiment could be sourced.

Claude Code ▸
Vertebral Anomalies and Variable Endocrine and T-cell Dysfunction (VETD; TBX2-related): Research Report
claude-haiku-5-5, claude-opus-5-5 9 citations 2026-10-15T11:14:53.158854

Vertebral Anomalies and Variable Endocrine and T-cell Dysfunction (VETD; TBX2-related): Research Report

Scope and caveats. VETD is an ultra-rare syndrome. Its definition rests on one 2018 paper describing four people (Liu et al., PMID:29726930). A few later reports describe other conditions caused by changes in the same gene (TBX2), and they widen the picture. Most of the biology behind the mechanism comes from mouse, zebrafish and fly experiments.

Two kinds of identifier in this report need care before use: - Ontology IDs (HPO, GO, CL, UBERON, NCIT) are leads only. The repository rules say every CURIE must be looked up and its label copied in the same step it is written. - PMIDs: those marked ✔ have a file in references_cache/ in this worktree. Those marked (unverified) were not fetched.

1. Disease information

Overview. VETD is an autosomal dominant malformation syndrome caused by damaging heterozygous variants in TBX2, a gene encoding a T-box transcription factor (17q23.2). It resembles DiGeorge syndrome (22q11.2 deletion syndrome). Features vary between patients: - vertebral segmentation defects, such as Klippel-Feil anomaly, hemivertebrae and fused ribs - endocrine problems: hypoparathyroidism, growth hormone deficiency, autoimmune thyroiditis - T-cell deficiency, with an absent or underdeveloped thymus in some patients - cleft palate and characteristic facial features - congenital heart defects - mild developmental or behavioral problems

The original paper frames it this way (PMID:29726930 ✔):

"We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants."

Identifiers

Resource ID
OMIM (phenotype) 618223
OMIM (gene) TBX2 *600747
MONDO MONDO:0032607
MedGen C4748741 (UID 1648299)
Disease Ontology DOID:0070345
KEGG Disease H02753
LOVD disease #06365
HGNC TBX2 is hgnc:11597 (verify with lookup)
Orphanet No ORPHA code found; search ORPHA directly before asserting there is none
ICD-10/ICD-11 No specific code. KEGG files it under ICD-11 "multiple developmental anomalies or syndromes"

Synonyms: VETD; TBX2-related DiGeorge-like syndrome (descriptive only). Some literature uses "TBX2-associated multisystem malformation disorder."

Source of the data. Everything comes from individual case reports, one undiagnosed-disease-network family, and one Finnish pedigree. There is no registry or EHR cohort.

2. Etiology

  • Cause: a germline heterozygous variant in TBX2 that partially or fully removes its function. The founding variants are p.Arg20Gln (inherited in one family) and p.Arg305His (de novo).
  • Both reduced TBX2's ability to repress its target genes and lowered TBX2 protein levels.
  • In fruit flies, both behaved as partial loss-of-function alleles (PMID:29726930 ✔): "Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles."
  • Modifier and dosage-partner genes: mouse genetics shows Tbx2 and Tbx3 compensate for each other, and that Tbx1, Tbx2 and Tbx3 act together in the pharyngeal region.
  • Losing alleles of Tbx2 and Tbx3 in combination gives defects that "are not simply additive" (PMID:35506352 ✔, limb).
  • Tbx1/Tbx2/Tbx3 interactions govern pharyngeal and arterial-pole development (PMID:22116936 ✔).
  • No human modifier has been shown.
  • Environmental, protective and gene-environment factors: none described. This is a developmental disorder with an entirely genetic cause.
  • Common-variant association: TBX2 rs882367 reaches genome-wide significance for sitting-height ratio. This comes from Mäkitie et al. citing a GWAS; the primary GWAS was not fetched.

3. Phenotypes

Frequencies are counts out of the four people in the founding report: three p.R20Q family members and one p.R305H proband (PMID:29726930; summary table reproduced in PMID:35311234 ✔). HPO features come from the OMIM clinical synopsis as listed by MedGen. All features are congenital or appear in childhood unless stated.

Feature Detail and frequency Suggested HPO label (look up the ID)
Vertebral segmentation anomalies R20Q: Klippel-Feil anomaly, rib fusions. R305H: fused thoracic vertebrae and hemivertebrae (4/4) Hemivertebrae; Klippel-Feil anomaly; Vertebral fusion; Rib fusion
Scoliosis and kyphosis Present in several; progressive spinal deformity Scoliosis; Kyphosis
Sprengel deformity R20Q family Congenital elevation of scapula (Sprengel)
Camptodactyly PIP contracture of 3rd and 4th fingers Contracture of the PIP joint of the 3rd finger / 4th finger
Short or webbed neck, low hairline Short neck; Webbed neck; Low anterior hairline
Cleft palate (± cleft lip) R20Q proband: unilateral cleft lip and palate; R305H: high narrow palate Cleft palate; Cleft lip; Narrow palate
Facial features Triangular face, hypertelorism, epicanthus, depressed nasal bridge, broad nasal tip, cupped low-set ears, overfolded helix Triangular face; Hypertelorism; Epicanthus; Depressed nasal bridge; Cupped ear; Low-set ears
Thymic aplasia and T-cell deficiency R20Q proband: "absent thymus with severe T-cell deficiency"; diagnosed with complete DiGeorge and given a thymus transplant at about 6 months (UDN page) Aplasia of the thymus; Decreased total T cell count; Abnormal B cell morphology
Hypoparathyroidism R20Q family Hypoparathyroidism
Autoimmune thyroiditis Proband: hypothyroid, later hyperthyroid phase Hashimoto thyroiditis
Growth hormone deficiency R305H Decreased response to growth hormone stimulation test
Short stature Height between the 2nd and 36th percentile Short stature
Congenital heart defects R20Q: ASD and PDA. R305H: double-outlet right ventricle with valvular pulmonary stenosis Atrial septal defect; Patent ductus arteriosus; Double outlet right ventricle; Pulmonic stenosis
Neurodevelopment and behavior Mild global developmental delay, autistic behaviors, ADHD; neonatal seizures in one; mild cognitive impairment (R305H) Mild global developmental delay; Autistic behavior; Attention deficit hyperactivity disorder; Seizure
Other Glabellar hemangioma; congenital ectopic pupil; brachycephaly as named

Quality of life. No formal measures (EQ-5D, SF-36) have been reported. The main burdens are: - in infancy, risk of life-threatening infection when the thymus is absent - heart surgery - progressive spinal deformity - lifelong hormone replacement

Phenotypes from related TBX2 variants. These may belong to the same spectrum or to separate disorders; see the lump/split note in §4. - p.Thr300Met, Finnish three-generation family (PMID:35311234 ✔): - codfish-shaped vertebrae with balloon-shaped discs - severe early-onset osteoarthritis, with hip replacement in the early 20s to 30s - empty sella without hormone deficiency (one member had mild thyrotoxicosis) - obesity, headaches, depression, reduced sitting-height ratio - p.Lys177* (de novo nonsense change): severe osteochondrodysplasia with developmental delay (PMID:36733940 ✔). - 17q23.2 duplication including TBX2: complex heart defect (VSD, coarctation, mitral stenosis), short or missing end bones of the fingers, cerebellar hypoplasia, growth restriction starting before birth, mild intellectual disability (PMID:20635360 ✔).

4. Genetic and molecular information

  • Gene: TBX2 (OMIM *600747; 17q23.2; transcript NM_005994.4). It encodes a T-box transcription factor that mainly represses its targets. Its DNA-binding T-box domain spans roughly residues 94–280.

Known variants

Variant Type Origin Effect Phenotype PMID
c.59G>A p.Arg20Gln Missense, N-terminal Inherited (AD; mother → 2 children) Partial loss of function; reduced repression and lower protein VETD (thymic aplasia, hypoparathyroidism, cleft, ASD/PDA) 29726930 ✔
p.Arg305His Missense, just after the T-box De novo Partial loss of function VETD (GH deficiency, fused vertebrae, DORV) 29726930 ✔
c.899C>T p.Thr300Met Missense Inherited (AD, 3 generations) Predicted damaging; not tested in the lab. gnomAD MAF 3.9×10⁻⁵ overall, 3.9×10⁻⁴ in Finns Osteochondrodysplasia with empty sella 35311234 ✔
c.529A>T p.Lys177* Nonsense, in the T-box De novo Predicted loss of function or nonsense-mediated decay; ACMG likely pathogenic Severe osteochondrodysplasia with developmental delay 36733940 ✔
c.977delA p.Asp326Alafs*42; c.987delC p.Ala330Argfs*38 Frameshift Inherited (AD, 2 Chinese families) Stable nuclear protein with about 80% less transcriptional activity; haploinsufficiency Progressive sensorineural hearing loss ± nystagmus, without other syndromic features 40962492 ✔
p.R608W, p.T249I, p.R616Q Missense Found only in cases (588 conotruncal heart defect cases vs 300 controls) Changed mRNA and protein levels Conotruncal heart defects Xie et al. 2018, Hum Genomics, PMID:30223900 (unverified)
17q23.2 duplication Copy-number gain De novo Proposed overexpression Heart and finger anomalies 20635360 ✔
17q23 deletion including TBX2 and TBX4 Copy-number loss — Haploinsufficiency of two genes Limb and musculoskeletal anomalies, microcephaly Nimmakayalu et al. 2011 (PMID not fetched)
  • ClinVar and ClinGen: no ClinGen gene-disease validity curation was found for TBX2–VETD. Do not record a validity tier; it would have to be copied from a source.
  • Lump/split note for curation.
  • The hearing-loss families are explicitly described as having "isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described TBX2-associated disorders" (PMID:40962492 ✔). They look like a separate allelic disorder.
  • The p.Thr300Met and p.Lys177* skeletal dysplasias share vertebral and facial features with VETD. Mäkitie et al. treat theirs as a TBX2 skeletal dysplasia that overlaps VETD. Treat them as part of the spectrum or as subtypes, and record the uncertainty.
  • Epigenetics: nothing disease-specific. Disrupting the antisense long non-coding RNA TBX2-AS1 has been linked to hearing impairment (cited in PMID:40962492).
  • Somatic origin: not applicable.

5. Environmental information

None known. There are no environmental, lifestyle or infectious causes. Infections are a complication of T-cell deficiency, not a cause.

6. Mechanism and pathophysiology

Causal chain

  1. A heterozygous damaging TBX2 variant (missense, nonsense or frameshift) leads to less functional TBX2 protein. Missense variants reduce protein amount and repressor activity; truncating variants are predicted to cause haploinsufficiency. (Shown in cell lines and flies for R20Q and R305H, PMID:29726930; shown for the frameshifts, PMID:40962492.)
  2. Less TBX2 results in weaker repression of target genes in tissues of the developing embryo where TBX2 acts. The pathway branches here:
  3. 2a. Pharyngeal and second-heart-field mesoderm. In mice, Tbx2/Tbx3 act with Tbx1 in the caudal pharyngeal region (PMID:22116936 ✔). Reduced dosage is inferred to disturb development of the third and fourth pharyngeal pouches and arches, which leads to thymic aplasia or hypoplasia (→ T-cell deficiency → infections) and parathyroid hypoplasia (→ hypoparathyroidism). (Inferred from the mouse pathway and the clinical resemblance to 22q11.2 deletion; no TBX2-specific thymus experiment has been done.)
  4. 2b. Heart. Tbx2 holds back chamber differentiation in the atrioventricular canal and is needed to septate the outflow tract (PMID:15459098 ✔). Tbx2/Tbx3 also drive AV-canal myocardium and endocardial cushion formation (PMID:22130515 ✔). Disruption results in septal defects (ASD) and outflow-tract defects (DORV, pulmonary stenosis). (Shown in mice; inferred in humans.)
  5. 2c. Palate. Tbx2 null mice and mice heterozygous for both Tbx2 and Tbx3 have cleft palate. In these mice the palatal shelves are smaller, with more proliferation and cell death and raised Bmp4 and Cyclin D1 (PMID:19769959 ✔). This leads to cleft palate.
  6. 2d. Axial skeleton and limb. TBX2 is expressed in hypertrophic chondrocytes and osteoblast lineages (reviewed in PMID:35311234). In the limb bud it ends the Shh/Fgf feedback loop by directly repressing Grem1 (PMID:23633963 ✔). Reduced dosage is inferred to cause errors in vertebral segmentation and endochondral ossification, giving hemivertebrae, fused vertebrae and ribs, codfish vertebrae, and early-onset osteoarthritis. (The vertebral mechanism is inferred; mouse limb findings show the role in digits.)
  7. 2e. Hypothalamic-pituitary axis. Tbx2 is expressed in the infundibulum of the ventral diencephalon (PMID:18534921 ✔). This may lead to growth hormone deficiency (R305H) and empty sella (T300M). (Inferred; no functional study.)
  8. 2f. Inner ear (allelic hearing-loss disorder). Tbx2 is a master regulator that makes inner hair cells distinct from outer hair cells (García-Añoveros et al., Nature 2022, PMID:35508658, unverified). Tbx2+/− mice develop progressive hearing loss, and their inner hair cells briefly misexpress an outer-hair-cell marker (PMID:40962492 ✔). This leads to progressive sensorineural hearing loss.
  9. Thyroid autoimmunity, such as Hashimoto thyroiditis, is plausibly downstream of thymic hypoplasia and poor central tolerance, as in partial DiGeorge syndrome. (Inferred.)

Details for curation

  • Molecular function: sequence-specific DNA-binding transcription repressor activity (GO "DNA-binding transcription repressor activity, RNA polymerase II-specific"). Biological processes to consider: outflow tract septum morphogenesis, atrioventricular canal development, palate development, thymus development, parathyroid gland development, regulation of chondrocyte differentiation, negative regulation of cell cycle. Tbx2 represses Cdkn2a/b and Cdkn1a, though Harrelson et al. found this was not required in the heart (PMID:15459098).
  • Cell types (CL leads): second heart field progenitor (Tbx2 misexpression impairs their deployment, PMID:19563797 ✔), cardiac muscle cell of the atrioventricular canal, pharyngeal endoderm and mesenchyme, palatal mesenchyme, chondrocyte or hypertrophic chondrocyte, osteoblast, thymic epithelial cell, parathyroid chief cell, T cell, cochlear inner hair cell.
  • Not yet studied: single-cell, multi-omic and CRISPR-screen data specific to this disease.
  • GEO datasets: none specific to VETD. Mouse Tbx2/Tbx3 ChIP-seq and expression profiles exist in PMID:22130515.

7. Anatomical structures affected

  • Primary: vertebral column and ribs; thymus; parathyroid glands; heart (interatrial septum, outflow tract, pulmonary valve, ductus arteriosus); secondary palate; face and ears.
  • Secondary: thyroid (autoimmunity); pituitary and sella turcica; joints (hip, knee) in the T300M family; brain (cerebellar hypoplasia in the duplication case).
  • Embryonic origins: pharyngeal arches and pouches 3 and 4, second heart field, somites and sclerotome.
  • Subcellular: nucleus. TBX2 is a nuclear transcription factor, and the frameshift proteins still localize to the nucleus.
  • Lateralization: cleft lip was unilateral in the proband. Other anomalies are midline or bilateral.

8. Temporal development

  • Onset: congenital (malformations, thymic aplasia). Endocrine features can appear in childhood: thyroiditis in childhood, and GH deficiency shown by slowing growth.
  • Course: a static malformation syndrome. Scoliosis or kyphosis and osteoarthritis (T300M) progress. The hearing loss in the allelic disorder is progressive.
  • Critical windows: early infancy for diagnosing T-cell deficiency and doing a thymus transplant; childhood for monitoring spinal deformity.

9. Inheritance and population

  • Inheritance: autosomal dominant. There is both inherited transmission (R20Q, mother to two children) and de novo occurrence (R305H, K177*).
  • Expressivity: variable. The mother and sister of the R20Q proband had milder versions of his features (UDN page).
  • Penetrance: incomplete penetrance has not been established for VETD. Nystagmus was incompletely penetrant in the hearing-loss families.
  • Founder effect: p.Thr300Met is about 10 times more frequent in Finns (gnomAD), which suggests a Finnish founder allele (PMID:35311234).
  • Prevalence: unknown, ultra-rare. Fewer than 10 individuals have published VETD-type syndromic features. Suggested record: prevalence_class ULTRA_RARE or NOT_YET_DOCUMENTED with measure_type: CASES_IN_LITERATURE.
  • Sex ratio: not determinable. Both sexes are affected.
  • Anticipation and consanguinity: not relevant.

10. Diagnostics

  • Clinical suspicion: a DiGeorge-like picture (conotruncal or septal heart defect, cleft palate, hypocalcemia or hypoparathyroidism, T-cell lymphopenia) in someone without a 22q11.2 deletion, especially when vertebral segmentation defects are also present.
  • Laboratory and immunology:
  • T-cell subsets (CD3/CD4/CD8), naive T cells (CD45RA), TRECs
  • immunoglobulins
  • calcium, phosphate, PTH
  • TSH, free T4, thyroid antibodies
  • IGF-1 and GH stimulation testing
  • Newborn screening: TREC-based SCID screening can detect the athymic form.
  • Imaging: spine X-ray, MRI or CT for hemivertebrae, fusions and codfish vertebrae; echocardiography; chest imaging for thymus; brain or pituitary MRI for empty sella.
  • Genetic testing:
  • First rule out 22q11.2 deletion with chromosomal microarray or MLPA. CMA also detects 17q23.2 copy-number changes.
  • Then exome or genome sequencing. Every published diagnosis came from exome or genome sequencing, through the UDN and research programs.
  • TBX2 is rarely on commercial DiGeorge-like or skeletal dysplasia panels. Hua et al. recommend adding it to hearing-loss panels.
  • Differential diagnosis: 22q11.2 deletion syndrome (TBX1); CHARGE syndrome (CHD7); 10p13–p14 deletion (HDR/DiGeorge-2); FOXN1 deficiency; Klippel-Feil syndromes (GDF6, MEOX1); spondylocostal dysostoses; TBX1 point-variant disease; ulnar-mammary syndrome (TBX3); other osteochondrodysplasias for the T300M phenotype.
  • No formal diagnostic criteria exist.

11. Outcome and prognosis

  • Survival data: none. In the founding family the proband survived after a thymus transplant and was 10 years old on the UDN page.
  • Main risks:
  • infection in complete thymic aplasia, which is fatal in infancy without transplant (general knowledge for complete DiGeorge, not TBX2-specific evidence)
  • complications of heart lesions
  • hypocalcemic seizures
  • progressive spinal deformity
  • early disabling osteoarthritis (T300M family, with joint replacement in the 20s and 30s)
  • Prognostic factors: severity of thymic and T-cell involvement and complexity of the heart lesion (inferred).

12. Treatment

There are no trials and no disease-specific therapy. Care is supportive and depends on which organs are involved. NCIT terms below are leads; confirm each one falls under NCIT:C25218.

Problem Intervention Suggested NCIT lead
Complete thymic aplasia Allogeneic cultured thymus tissue implantation; the R20Q proband received a thymus transplant. Rethymic® is FDA-approved (2021) for congenital athymia Organ Transplantation (C15289) or a more specific term; modality CELL_THERAPY
Partial T-cell deficiency Infection prophylaxis, IVIG if needed, avoid live vaccines, irradiated blood products Supportive Care (C15747); Pharmacotherapy with immunoglobulin agent
Hypoparathyroidism Calcium plus calcitriol; recombinant PTH where indicated Pharmacotherapy (C15986) + therapeutic_agent calcitriol (CHEBI)
GH deficiency Recombinant growth hormone Pharmacotherapy + somatropin
Hypothyroidism / thyroiditis Levothyroxine; antithyroid drugs in a hyperthyroid phase Pharmacotherapy + levothyroxine
Heart defects Surgical or catheter repair Surgical Procedure (C15329)
Cleft palate Palatoplasty and speech therapy Surgical Procedure; Speech language therapy
Scoliosis/kyphosis; osteoarthritis Bracing, spinal fusion; hip arthroplasty (T300M) Orthopedic Surgical Procedure (C16186)
Development and behavior Early intervention, ADHD management Behavioral / rehabilitation terms
Hearing loss (allelic disorder) Hearing aids or cochlear implant Surgical Procedure + device qualifier
  • Pharmacogenomics, gene therapy, RNA therapy: none.
  • Research model: an iPSC line (IRDWCHi001-A) from a p.Asp326Alafs*42 carrier is available for disease modeling (PMID:41512733 ✔).

13. Prevention

  • Primary prevention: not applicable.
  • Secondary prevention: TREC newborn screening catches the T-cell deficiency early. Consider cascade testing of relatives once a familial variant is known, because expressivity varies and mildly affected parents are easy to miss.
  • Tertiary prevention: regular monitoring of calcium, PTH, thyroid function, growth and the spine; infection prophylaxis.
  • Genetic counseling: affected individuals have a 50% chance of passing the variant to each child. Prenatal or preimplantation testing is possible once the variant is known. For apparently de novo cases, mention the possibility of parental germline mosaicism.

14. Other species and natural disease

  • No naturally occurring TBX2 disease has been reported in animals (OMIA not searched in detail).
  • Orthologs: mouse Tbx2 (chromosome 11); zebrafish tbx2a and tbx2b (ZFIN ZDB-GENE-990917-4 is one of these); Drosophila bifid/omb (the fly T-box gene used in PMID:29726930).
  • The T-box domain is highly conserved: about 96% of human and mouse T-box residues are identical (PMID:36733940).
  • Not zoonotic.

15. Model organisms

Model Phenotype and relevance PMID
Tbx2−/− mouse Embryonic lethal; AV canal and outflow tract septation defects; extra digit 4 on the hindlimb. Heterozygous mice appear normal, a mismatch with the human dominant disease 15459098 ✔
Tbx2−/− and Tbx2+/−;Tbx3+/− mouse Cleft palate 19769959 ✔
Tbx2/Tbx3 compound mutants AV canal myocardium and endocardial cushion failure; limb defects that depend on dosage 22130515 ✔, 35506352 ✔
Tbx1/Tbx2/Tbx3 genetic interaction Pharyngeal and arterial-pole morphogenesis; the pathway behind DiGeorge-like features 22116936 ✔
Conditional Tbx2 overexpression in the myocardium Less proliferation; impaired deployment of second-heart-field cells into the outflow tract 19563797 ✔
Limb-specific Tbx2 gain or loss Grem1 repression ends Shh/Fgf signaling; abnormal digit number 23633963 ✔
Tbx2+/− and knock-in mice (hearing) Progressive hearing loss; inner hair cells misexpress an outer-hair-cell marker. Supports haploinsufficiency 40962492 ✔
Cochlear conditional Tbx2 KO Inner hair cells convert to outer hair cells 35508658 (unverified)
Drosophila heterologous overexpression R20Q and R305H are partial loss of function 29726930 ✔
Human iPSC line IRDWCHi001-A Hearing-loss disease modeling 41512733 ✔

Model limitations to record

  • Tbx2 heterozygous mice do not reproduce the human dominant malformation syndrome, as far as the published reports show (PMID:15459098). This fits a HUMAN_MODEL_MISMATCH discussion. It also suggests human missense alleles may act through more than simple haploinsufficiency, or that humans are more sensitive to TBX2 dosage. Both remain hypotheses.
  • No model has directly tested thymus or parathyroid development with Tbx2 alone.

Key evidence quotes from cached abstracts

  • PMID:29726930: "In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2."
  • PMID:15459098: "Mice heterozygous for a Tbx2 null mutation appear normal but homozygous embryos reveal a crucial role for Tbx2 during cardiac development."
  • PMID:19769959: "Mice homozygous mutant for Tbx2 and mice double heterozygous for Tbx2 and Tbx3 exhibit a cleft palate phenotype"
  • PMID:35311234: "Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities."
  • PMID:36733940: "Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2."
  • PMID:40962492: "In vivo, heterozygous Tbx2 knockout mice (Tbx2+/- ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism."
  • PMID:20635360: "A SNP-array analysis detected a de novo duplication of 17q23.2, encompassing the TBX2 gene."

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 2
Quoted claims not found in source 0
References weighed for topical relevance 17
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 3
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0032607 (1 mention) - the report calls it "MONDO"; MONDO calls it vertebral anomalies and variable endocrine and T-cell dysfunction
  • DOID:0070345 (4 mentions) - the report calls it "Disease Ontology"; DOID calls it vertebral anomalies and variable endocrine and T-cell dysfunction