Main clinical features
Complete HEY2 loss resulting from a homozygous loss-of-function variant causes critical CHD, whereas the majority of heterozygous carriers show a spectrum of cardiovascular diseases (CVD), with incomplete penetrance and variable expressivity.

Autosomal recessive inheritance leads to severe CHD, whereas autosomal dominant inheritance seems to result in a higher risk of CHD, FTAA, myocardial hypertrabeculation and valve abnormalities. However, more patient data is needed to examine the risk and consequences for carriers of a likely pathogenic heterozygous HEY2 variant more precisely.

Prevalence is yet to be determined; but in a cohort of 2685 individuals with CHD, four (0.0015%) had a rare, potentially pathogenic (CADD>20) heterozygous variant in HEY2 that affected the functional domains. Furthermore, two individuals from a cohort of 326 individuals with FTAA and dissections had such a variant (0.0061%) (van Walree et al., Genetics in Medicine 2020).