Mechanisms of DiseaseRole of TBX1 in human del22q11.2 syndrome
Introduction
Del22q11.2 syndrome, with an incidence of 1 in every 4000–5000 births,1 encompasses DiGeorge's syndrome2 with conotruncal anomaly face and conotruncal anomaly face syndrome3, 4/velo-cardio-facial syndrome.5 It is a contiguous gene syndrome characterised by many abnormalities, including cardiac outflow tract anomalies, absence or hypoplasia of the thymus and parathyroid glands, nasal voice (often associated with cleft palate or submucosal cleft palate), and facial dysmorphism, known as conotruncal anomaly face. Patients with this syndrome who have either hemizygous deletion of the 3-Mb or 1·5-Mb interval, including 24–30 genes on chromosome 22q11.2, all have similar phenotypes.6, 7, 8 However, the few patients who have different deletions or rearrangements in the region have not been informative in localising disease genes because these arrangements are non-overlapping.7, 8 Therefore, it has not been possible to correlate these genes with the cause of this syndrome. One of the key genes, TBX1, encodes a T-box transcription factor, which is known to have an essential role in early vertebrate development. TBX1 has been suggested as a candidate gene for del22q11.2 syndrome,9, 10, 11 however, no mutation of TBX1 was identified in more than 250 patients with a clinical suspicion of del22q11.2 syndrome but without a deletion or other detectable rearrangement.9, 12, 13 Thus, in this study, we aimed to localise the TBX1 mutation in patients in whom we had carefully assessed the phenotype.
Section snippets
Clinical evaluation
All assessments were done with the approval of the internal ethics committee of Tokyo Women's Medical University, Japan. After written informed consent was obtained, we assessed each patient by history and physical examination, and in some cases reviewed their medical records. The usual manifestations of conotruncal anomaly face syndrome were diagnosed independently by three cardiologists who have been diagnosing conotruncal anomaly face syndrome for more than 20 years, and have become highly
Statistical analysis
We used X2 analysis to assess for significance in the frequency of the TBX1 mutation. The probability was deemed significant if the p value was less than 0·05.
Role of the funding source
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
108 (46%) of the 235 probands with clinically diagnosed conotruncal anomaly face syndrome or DiGeorge's syndrome with conotruncal anomaly face were male. In ten probands from eight sporadic cases (seven with conotruncal anomaly face syndrome and one with DiGeorge's syndrome) and from two with familial conotruncal anomaly face syndrome (mother, female proband, and younger brother; mother and female proband) without the 22q11.2 deletion six were male.
In this and a previous study,15 we noted that
Discussion
Our results imply that the TBX1 mutation is responsible for five major phenotypes—ie, abnormal facies (conotruncal anomaly face), cardiac defects, thymic hypoplasia, velopharyngeal insufficiency with cleft palate and parathyroid dysfunction with hypocalcaemia, which are major phenotypes in del22q11.2 syndrome, but not typical mental retardation that is commonly seen in patients with del22q11.2 syndrome. Patient F1 had three major phenotypes, patient F2 had all five major phenotypes and in
GLOSSARY
- contiguous gene syndrome
- A contiguous gene syndrome is characterised by multiple, apparently unrelated, clinical features caused by deletion of multiple adjacent genes; each of the individual genes within a contiguous region, when mutated, gives rise to a distinct feature.
- haploinsufficiency
- When loss of function of one gene copy leads to an abnormal phenotype.
- t-box gene family
- T-box gene family of transcription factors has essential roles in organogenesis and pattern formation in both vertebrate
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