ELECTRONIC LETTER Assessment of association between variants and haplotypes of the remaining TBX1 gene and manifestations of congenital heart defects in 22q11.2 deletion patients

D eletion 22q11.2, commonly associated with DiGeorge or velocardiofacial syndrome (DGS/VCFS; MIM 188400), is a major cause of congenital heart disease, accounting for about 5% of all congenital heart defects in live births. However, the presence of the deletion does not allow one to predict the phenotype, as patients with a 22q11.2 deletion usually show a broad range of clinical variation despite a common deletion size of 3 Mb. Observations of phenotypic discordance—especially in the heart manifestations—in monozygotic twins concordant for 22q11.2 deletion have led some investigators to postulate that the clinical variability in this disorder is generally not caused by genetic factors. Nevertheless, studies of Df1/+ mice, which model the 22q11.2 deletion from Tbx1 haploinsufficiency, showed that the penetrance of cardiovascular defects varies widely in different genetic backgrounds, thus revealing for the first time the presence of major genetic control over the phenotypic variability of 22q11.2 deletion. Subsequently, Vitelli et al showed that Tbx1; Fgf8 double mutants present with a significantly higher penetrance of aortic arch artery defects than Tbx1; Fgf8 mutants, while Tbx1; Fgf8 animals are normal. The underlying mechanism in humans is still unclear, however. There is no evidence for an imprinting effect, and we previously excluded somatic second hit deletions in tissues derived from the pharyngeal arch as a common mechanism for the clinical variability with respect to congenital heart disease. Recently, a preliminary association between the expression of congenital heart defects in 22q11.2 deletion patients and a certain single nucleotide polymorphism (SNP) haplotype within the promotor region of VEGF was reported. However, apart from non-allelic modifiers, unmasking of recessive mutations by hemizygosity has also been considered a possible modifying factor. 13 14 Prompted by recent reports by several groups showing that mice with Tbx1 haploinsufficiency—which is located within the DiGeorge/VCFS region in 22q11.2—have cardiovascular defects, we investigated whether mutations, variants, or common haplotypes within the remaining TBX1 gene could modify the expression of the heart phenotype in patients with 22q11.2 deletion.