Molecular Characteristics

In a large family from a genetically isolated population, a rare (MAF 1.1×10−5 in Genome Aggregation Database v.2.1.1) two base pair deletion in exon 4 of HEY2 (NM_012259.3, c.318_319delAG, p.G108*, Chr6[GRCh37]:g.126075682_126075683del) variant was identified, leading to frameshift and predicted early stop codon. The suspected pathophysiologic mechanism is that pathogenic variants in HEY2, which is a cardiac transcription factor with a repressive function, lead to dysregulation of expression of target genes. The p.G108* variant led to overexpression of a target gene and therefore indicates HEY2 loss-of-function. Other identified heterozygous variants in individuals with CHD or FTAA and dissections led to both over- and underexpression of a target gene, indicating that both gain and loss-of-function of HEY2 can lead to CVD. There is some indication that mainly variants in/leading to loss of the HEY2 functional domains are pathogenic, but more evidence is required to determine a clear association.