The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first-to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS.The 22q11.2 deletion syndrome (22q11DS) is a common, multisystem disorder associated with microdeletion 22q11.2 that occurs at an estimated prevalence of 1/4,000 live births.1 Congenital heart disease (CHD) is a classic feature of 22q11.2DS, found in about 40% of patients.2-5 Conotruncal anomalies such as tetralogy of Fallot (TOF), interrupted aortic arch, and truncus arteriosus have been most strongly associated.6,7 Multiple factors are CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptthought to affect the expression of CHD in patients with 22q11DS. These include the hemizygosity of the 45 genes in the 22q11.2 deletion region and interaction of the effects of hemizygosity with genetic variants both in the intact chromosome 22 and elsewhere in the genome.8,9 In families of probands with 22q11.2 deletions, an elevated prevalence of CHD in relatives without 22q11.2 deletions would support this hypothesis of genetic interaction. Two previous pediatric studies have suggested such an elevated prevalence of CHD.10,11 However these studies involved in total just 6 first-degree relatives with CHD and did not report on the parental origin of the 22q11.2 deletion. In the present study, a wellcharacterized group of adults with 22q11DS was examined for a family history of CHD in their relatives...