We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome.
These include the 3-Mb region commonly deleted in DiGeorge/velocardiofacial syndrome (DGS/VCFS), the cat eye syndrome (CES) region, and more distal regions in 22q11 that have recently been shown to be deleted.
Here, the genetic pathways regulating cardiac neural crest development are reviewed and the evidence implicating TBX1 and other genes on chromosome 22q11 in the pathogenesis of DiGeorge syndrome is summarized.
The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of TBX1, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations.
PRODH maps to 22q11 in the region deleted in the velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS) and encodes proline oxidase (POX), a mitochondrial inner-membrane enzyme that catalyzes the first step in the proline degradation pathway.
To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients.
We showed that inactivation of Bmp4 from Tbx1-expressing cells leads to the spectrum of deformities resembling the cardiovascular defects observed in human DiGeorge syndrome patients.
The low-copy repeat (LCR) is a new class of repetitive DNA element and has been implicated in many human disorders, including DiGeorge/velocardiofacial syndrome (DGS/VCFS).
This report describes a newborn girl presenting with some of the common features of DiGeorge syndrome/velocardiofacial syndrome (DGS/VCFS), including hypocalcemia, atrial septal defect, and aortic stenosis.
DiGeorge/velocardiofacial syndrome (DGS/VCFS) is a disorder caused by a 22q11.2 deletion mediated by non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs).
Mutations in human T-box genes TBX3, TBX5, and TBX1 cause severe genetic disorders known as Ulnar-Mammary syndrome (UMS), Holt-Oram syndrome (HOS), and DiGeorge syndrome, respectively.
FISH studies using 4 locus-specific DNA probes in the 22q11.2 region (N25 probe to detect the D22S75 locus within the velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS) critical region, a clone to detect the Bid locus just distal to the cat eye syndrome (CES) critical region and two clones 77H2 and 109L3 to detect the proximal end of the CES critical region, (CECR2 and CECR7), did not reveal any hybridization signal with the marker chromosome.
Deletions within 22q11 have been associated with a wide variety of birth defects embraced by the acronym CATCH22 and including the DiGeorge syndrome, Shprintzen syndrome (velocardiofacial syndrome) and congenital heart disease.
Schizophrenia or schizoaffective disorders are quite common features in patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2.
Shprintzen syndrome (velo-cardio-facial, VCFS) is a very rare morbid entity, seen in either familial or sporadic forms, with major clinical findings such as facial dysmorphism, cleft palate, cardiovascular (especially conotruncal-anomalies), mild/moderate mental retardation, or, more commonly, observed learning difficulty.
Most DGS cases are caused by a heterozygous chromosomal deletion del22q11, and the search for haploinsufficient genes has been successful in mice and led to the discovery of Tbx1 as a major player in the development of the pharyngeal arches and pouches.
Schizophrenia (SCZD) or schizoaffective disorders are quite common features in patients with DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of chromosome 22q11.2 aploinsufficiency.
Children with 22q11.2 microdeletions (Velocardiofacial Syndrome; VCFS) have previously been shown to exhibit learning deficits and elevated rates of psychopathology.
The Tbx1 genetic pathway and the cell biology of tissues contributing to pharyngeal arch arteries and cardiac outflow tract are the foundation for understanding congenital heart disease in DiGeorge syndrome.