There is more to it than just congenital heart defects – The phenotypic spectrum of TAB2-related syndrome

Congenital heart defects (CHD) are the most common birth defect and disease-causing variant in TAB2 have found to be associated with isolated CHD. Recently, it became evident that pathogenic, mostly loss-of-function variants in TAB2 can also cause syndromic CHD that includes connective tissue anomalies. The number of published cases is limited posing a challenge for counseling affected patients and their relatives.Cases in whom whole exome sequencing was executed at our institute between January 2015 and June 2021 were screened for disease-causing variants in TAB2. Additionally, a PubMed-based review of the literature was performed in December 2021 in order to give an updated clinical overview of the TAB2-associated phenotypic spectrum, including our cases.We identified three cases with syndromic CHD caused by different heterozygous loss-of-function variants in TAB2. In one of these cases, the variant was inherited by a healthy father. A comparison with published cases highlights that most patients were affected by structural and/or arrhythmic heart disease (about 90%) while about two third of all cases had syndromic comorbidity especially connective tissue defects and dysmorphic abnormalities.Our findings indicate a variable expressivity as well as reduced penetrance of TAB2-associated CHD. Disease-causing variants in TAB2 should be considered in cases with isolated CHD but also in syndromic CHD with connective tissue abnormalities. However, prediction of the patients' clinical outcome solely based on the variant in TAB2 is still extremely challenging.