Emanuela Conti

[John]

Thankyou for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Conotruncal defects (CTDs) represent an important class of congenital heart diseases. Although they are mostly considered as complex, multifactorial disorders,1 a number of familial cases suggesting Mendelian inheritance have been described.2,3 CTDs, primarily interrupted aortic arch, persistent truncus arteriosus and tetralogy of Fallot (ToF), often occur in DiGeorge/Velo-cardio-facial syndrome (DGS/VCFS) patients with chromosome 22q11.2 deletion (del22q).4 However, del22q is very rare in isolated CTDs. In a cohort of 628 CTD patients we found only a single case of del22q.5 Even if recent studies have reported nonsyndromic ToF with NKX2.5 and JAG1 gene mutations,3,6 single-gene defects are likely to account for a very minority of CTD cases. In addition, the exclusion of del22q does not modify the recurrence risk in isolated non-syndromic CTDs.7 All the evidences, therefore, agree with the multifactorial model of transmission for isolated CTDs and suggest that many genes and pathogenetic mechanisms may be at work.

The TBX1 gene maps to the commonly deleted DGS/VCFS region on chromosome 22q11.2 and codes for a transcription factor belonging to the T-box family,8 probably required for growth and septation of the conotruncus.9 Mice hemizygous at the Tbx1 locus show a remarkable incidence of heart outflow tract anomalies, of the same type found in DGS/VCFS patients,10,11 suggesting a role of TBX1 in the pathogenesis of human CTDs.10,11,12 However, a few independent TBX1 gene mutation screenings in DGS/VCFS patients without del22q turn out negative.8,10 Gong et al13 have investigated TBX1 both in nondeleted patients with features of DGS/VCFS and in a series of subjects with isolated CTDs, including aortic arch anomalies, which can occur in DGS/VCFS individuals. They found a few rare TBX1 variants in four DGS/VCFS patients and in three isolated CTDs, but a functional role for these variants was not demonstrated. In order to better address the issue of the link between TBX1 and isolated CTDs, we screened TBX1 in a large sample of patients, including some peculiar anatomical CTD subtypes which were not represented in the mutation screening previously performed.13

These findings, while agreeing with most of the previous studies on DGS/VCFS patients without 22q11 deletion, apparently contrast those observed by Gong et al,13 who reported rare TBX1 variants in isolated aortic arch anomalies. All the TBX1 variants involved a newly discovered exon 9C, which was not screened in the previous negative studies. As remarked by Gong et al13 in their report, TBX1 mutations may be extremely rare, accounting only for a few CTD cases. Together with a quite different distribution of the CTD subtypes in our sample, it may explain the diverging results between the two studies.

The TBX1 gene variations so far reported on isolated CTDs are either polymorphisms, or changes with doubtful functional value.20 We cannot anyway rule out the possibility that some of these variants, even with wide distribution in the population, are somehow involved in the pathogenesis of the patients' heart malformations, interacting with other genetic and nongenetic factors, not strictly associated with the DGS/VCFS region, in accordance with the multifactorial model. Future functional studies will address this issue.

In conclusion, the present study does not support a major role of the TBX1 gene in the pathogenesis of human nonsyndromic CTDs. TBX1 sequence variations are not likely to represent causative factors of this type of human cardiac defects.

3a8082e126