Role of TBX1 in human del22q11.2 syndrome

doi:10.1016/S0140-6736(03)14632-6

The Lancet

Volume 362, Issue 9393, 25 October 2003, Pages 1366-1373

https://doi.org/10.1016/S0140-6736(03)14632-6 Get rights and content

Summary

Background

Del22q11.2 syndrome is the most frequent known chromosomal microdeletion syndrome, with an incidence of 1 in 4000–5000 livebirths. It is characterised by a 3-Mb deletion on chromosome 22q11.2, cardiac abnormalities, T-cell deficits, cleft palate facial anomalies, and hypocalcaemia. At least 30 genes have been mapped to the deleted region. However, the association of these genes with the cause of this syndrome is not clearly understood.

Methods

To test for the chromosomal deletion at 22q11.2, we did fluorescence in-situ hybridisation analysis with ten probes on 22q11.2 in 235 unrelated patients with clinically diagnosed del22q11.2 syndrome. To investigate mutations in the coding sequence of TBX1, we also did genetic analysis in 13 patients from ten families who have the 22q11.2 syndrome phenotype but no detectable deletion of 22q11.2.

Findings

96% (225 of 235) of patients had a defined 1·5–3-Mb deletion at 22q11.2. 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. We did not record these three mutations in 555 healthy controls (1110 chromosomes; p<0·0001).

Interpretation

Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q112 syndrome. Therefore, we conclude that TBX1 is a major genetic determinant of the 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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Mechanisms of DiseaseRole of TBX1 in human del22q11.2 syndrome

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Clinical evaluation

Statistical analysis

Role of the funding source

Results

Discussion

GLOSSARY

Cell

Gene

Gene

The clinical significance of 22q11 deletion

Discussion on a new concept of the cellular basis of immunity

J Pediatr

Facial appearance of patients with conotruncal anomalies

Pediatr Jpn

Etiologic categorization of common congenital heart disease

A new syndrome involving cleft palate, cardiac anomalies, typical facies and learning disabilities: velo-cardio-facial syndrome

Cleft Palate J

The 22q11 deletion syndromes

Hum Mol Genet

Chromosomal microdeletions: dissectiog del 22q11 syndrome

Nat Rev Genet

The 22q11.2 deletion syndrome

Keio J Med

Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice

Nature

DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1

Nat Genet

Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects

J Med Genet

DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 Gene

Eur J Hum Genet

Mechanisms of Disease
Role of TBX1 in human del22q11.2 syndrome