In mice, heterozygous and homozygous loss-of-function (LOF) mutations in Tbx1 (the murine ortholog of a gene present in the DiGeorge critical region [DGCR] on human chromosome 22q11.2) resulted in anomalies of the cardiac outflow tract, thymic and parathyroid gland abnormalities, and craniofacial defects. Nevertheless, previous investigators have been unable to document mutations in TBX1 in patients with a DiGeorge–like phenotype. The authors demonstrate that heterozygous LOF mutations in TBX1 can be responsible for the major clinical manifestations of the DiGeorge (DGS-hypoparathyroidism, thymic dysfunction, and cardiovascular anomalies) and conotruncal anomaly face syndromes (CAFS). They present an extremely carefully clinically characterized cohort of 235 Japanese patients with either DGS or CAFS. Fluorescence in-situ hybridization with site specific probes (FISH) analysis revealed microdeletions in the DiGeorge critical region of chromosome 22q11.2 in 225 (96%) patients. In 3 patients in whom no microdeletion of chromosome 22q11.2 could be detected despite examination with multiple probes, mutations in TBX1 were identified: exon 4:443T6A leading to Phe148Tyr; exon 8: 928G6A leading to Gly310Ser; exon 9: 1223delC leading to a stop signal at codon 459 and truncated product. TBX1 is a member of a family of T-box transcription factors important for specifying mesodermal differentiation. It is a 10–exon gene that is transcribed into 3 products (TBX1A, TBX1B, TBX1C); the first 2 mutations would affect all products while the third would alter only TBX1C. Clinical correlation revealed that those patients with the first 2 mutations had classical CAFS and DGS, respectively; the patient with the third mutation had a less severe form of CAFS. These observations suggest that the clinical manifestations of the DGS/CAFS depend in part upon the extent of TBX1 loss.
Yagi H, Furutani Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet. 2003;362:1366-1373.
Editor’s Comment : This report not only identifies TBX1 as an important determinant of DGS/CAFS, it also demonstrates the importance of a careful and complete clinical description of a complex and multidimensional clinical disorder. Twenty-five years of experience in treating patients with illnesses associated with microdeletions of chromosome 22q11.2 enabled these investigators to precisely define specific clinical criteria for the diagnoses of DGS/CAFS; they identified several abnormalities of the face that typified these patients (Figure). Thus, they were able to study patients who clearly had either DGS or CAFS. Therefore, LOF mutations in TBX1 are associated with 5 phenotypes: abnormal face, velopharyngeal insufficiency, cardiac outflow anomalies, and thymic and parathyroid dysfunction. They are not associated with developmental delay often encountered in patients with DGS/CAFS, implying that another gene(s) in the DGCR is likely responsible for this problem. Mutations in TBX1 were not detected in other subjects with DGS/CAFS, indicating there may be abnormalities in the non–coding region of this gene or that this disorder is polygenic in origin. In this regard, experimental deletion of Fgf8 leads to a murine phenotype quite similar to that of the DGS/CAFS, suggesting that the products of TBX1 may regulate the transcription of this gene. An interesting commentary accompanies this report. 1
Allen W. Root, MD
References - (linked to )
1. Baldini A. Lancet. 2003;362:1342-1343.