TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay.

Congenital heart defects (CHD) are the most commonly occurring birth defect and can occur in isolation or with additional clinical features comprising a genetic syndrome. Autosomal dominant variants in TAB2 are recognized by the American Heart Association as causing nonsyndromic CHD, however, emerging data point to additional, extra-cardiac features associated with TAB2 variants. We identified 15 newly reported individuals with pathogenic TAB2 variants and reviewed an additional 24 subjects with TAB2 variants in the literature. Analysis showed 64% (25/39) of individuals with disease resulting from TAB2 single nucleotide variants (SNV) had syndromic CHD or adult-onset cardiomyopathy with one or more extra-cardiac features. The most commonly co-occurring features with CHD or cardiomyopathy were facial dysmorphism, skeletal and connective tissue defects and most subjects with TAB2 variants present as a connective tissue disorder. Notably, 53% (8/15) of our cohort displayed developmental delay and we suspect this may be a previously unappreciated feature of TAB2 disease. We describe the largest cohort of subjects with TAB2 SNV and show that in addition to heart disease, features across multiple systems are present in most TAB2 cases. In light of our findings, we recommend that TAB2 be included on the list of genes that cause syndromic CHD, adult-onset cardiomyopathy, and connective tissue disorder.