TBX1 is the gene on chromosome 22q11.21, which encodes T-box 1 (OMIM: 602054, UniProtKB: O43435), a putative transcription regulator involved in development, which is required for normal development of the pharyngeal arch arteries.
Synonyms CAFS, CATCH22, CTHM, DGCR, DGS, DORV, TBX1C, TGA, VCF, VCFS
Molecular pathology Defects of TBX1 cause:
DiGeorge syndrome A common (1:4000 in the general population) autosomal dominant disorder characterised by:
– Hypocalcemia due to hypoplasia of parathyroid glands
– Underdeveloped-hypoplastic thymus with T-cell immunodeficiency; and
– Conotruncal–outflow tract–heart defect
Also present are distinctive facies, cleft palate, other congenital heart defects, learning disabilities, and 180 other clinical findings, including head and neck deformities due to defects of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches. Deletions in the same region of chromosome 22q11 as DiGeorge syndrome–DGS cause velocardiofacial syndrome (OMIM:192430); conotruncal anomaly face (Takao syndrome); and isolated outflow tract defects of the heart including tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch, prompting one cardiologist/Einstein to suggest we should use collective acronym CATCH22 for the whole magilla (good luck with that, Al).
Defective TBX1 is one of multiple genes involved in several other conditions primarily characterised by congenital heart disorders, see below bullet-pointed conditions:
Tetralogy of Fallot image from New Medical Terms
• Tetralogy of Fallot
(left image normal heart, right tetralogy) A congenital cyanotic heart disorder, defined by the tetralogy of:
– Obstruction of right ventricular outflow
– Ventricular septal defect
– Right ventricular hypertrophy
– Overriding aorta
Risk factors Maternal rubella, viral illness during pregnancy, poor prenatal nutrition, maternal alcoholism, mother > age 40, gestational diabetes, trisomy 21. Where a specific gene is involved (see below, molecular pathology), it is inherited in an autosomal dominant fashion
Clinical findings At birth, infants are not cyanotic, but later develop episodic cyanosis from crying or feeding–called “Tet spells”
The 32 year actuarial survival of patients with a TOF was 86%–who had a Blalock-Taussig palliative shunt prior to repair compared with an expected rate of 96% in an age– and sex–matched population
Molecular pathology Defects of:
• GATA4, which encodes a zinc-finger transcription activator that plays a key role in cardiac development, regulates genes involved in embryogenesis and myocardial differentiation and function, and is required for testicular development
• GATA6, which encodes a zinc-finger transcription factor thought to play a key role in regulating proliferation and terminal differentiation in the gastric epithelium and in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression
• GDF1, which encodes a member of the bone morphogenetic protein family and the TGF-beta superfamily, that regulate cell growth and differentiation; GDF1 is thought to be involved in establishing left-right asymmetry in the early embryo, and in neural development in later embryos
• JAG1, which encodes a receptor ligand that plays a role in mediating Notch signaling involved in cell-fate decisions during hematopoiesis and cardiovascular development,
• NKX2-5, which encodes a homeobox transcription factor, implicated in commitment to and/or differentiation of the myocardial lineage
• TBX1, which encodes a transcription regulator involved in development, and required for normal development of the pharyngeal arch arteries
• ZFPM2, which encodes a transcription factor that modulates the activity of GATA proteins that are key regulators of hematopoiesis and cardiogenesis,
all play a causative role in tetraology of Fallot.
• Velocardiofacial syndrome
An autosomal dominant condition, most commonly arising as a spontaneous mutation, which is characterised by cleft palate, cardiac defects–especially ventricular septal defect, typical facies–i.e., prominent tubular nose, narrow palpebral fissures, and slightly retruded mandible, and learning disabilities. Less common features included microcephaly, mental retardation, short stature, slender hands and digits, minor auricular anomalies, inguinal hernia and Pierre Robin syndrome.
Molecular pathology Defects, in particular haploinsufficiency of TBX1, which encodes a DNA-binding domain known as the T-box that regulates embryonic development, cause velocardiofacial syndrome and DiGeorge syndrome, the chromosome region for which—DGCR—also maps to 22q11, are thought to represent different clinical manifestations of the same defective gene and that DiGeorge syndrome is due to reduced gene dosage. Defects of CLDN5, which encodes claudin 5, have also been linked to velocardiofacial syndrome. Other genes lost in chromosome 22q11.2 deletion include that for the putative transcription factor TUPLE1. A collective acronym such as CATCH22 may reduce the confusion relating to the differing presentations of chromosomal losses in this region, which manifest themselves as velocardiofacial (aka Shprintzen) syndrome), conotruncal anomaly face (aka Takao) syndrome, and isolated outflow tract defects of the heart including tetralogy of Fallot and truncus arteriosus.
• Conotruncal heart malformations
A group of congenital heart defects characterised by cardiac outflow tract defects–e.g., tetralogy of Fallot, pulmonary atresia, double-outlet right ventricle*, truncus arteriosus communis†, aortic arch anomalies and transposition of great arteries‡.
*Pulmonary artery and aorta both arise from the right ventricle †Single outflow tract instead of a separate aorta and pulmonary artery ‡Aorta arises from the right ventricle; pulmonary artery from the left ventricle.
• GATA6—which encodes a zinc-finger transcription factor thought to play a key role in regulating proliferation and terminal differentiation in the gastric epithelium and in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression—cause persistent truncus arteriosus
• GDF1—which encodes a member of the bone morphogenetic protein family and the TGF-beta superfamily, that regulate cell growth and differentiation; GDF1 is thought to be involved in establishing left-right asymmetry in the early embryo, and in neural development in later embryos—cause double-outlet right ventricle
• NKX2-5—which encodes a homeobox transcription factor implicated in commitment to and/or differentiation of the myocardial lineage—cause conotruncal heart malformation—variable
• NKX2-6—which encodes a vertebrate homolog of Drosophila ‘tinman’, and essential for development of the heart-like dorsal vessel. It is a transcription activator and, with NKX2-5, may play a role in the embryonic development of pharyngeal and cardiac structures—cause conotruncal heart malformations and persistent truncus arteriosus
• TBX1—which encodes a transcription regulator involved in development, and required for normal development of the pharyngeal arch arteries—cause conotruncal anomaly face syndrome
Other genes implicated in conotruncal heart malformations include CFC1 and ZPFM2