Introduction: The ACMG recommends reporting incidentally discovered pathogenic variants in aortopathy genes. We investigated the electronic health records (EHR) to assess phenotypic correlates of pathogenic/likely pathogenic (P/LP) variants in 10 genes related to hereditary aortopathy.
Methods: The 10 aortopathy genes (Table) were sequenced in 2,344 individuals participating in the Mayo Return of Actionable Variants Empirical (RAVE) study. Of 1092 individuals with transthoracic echocardiography (TTE) data in the EHR, 26 were P/LP variant carriers including one with Marfan syndrome (MFS). After excluding this patient, for each P/LP variant carrier, we randomly selected 2 to 5 non-carriers matching by referral diagnoses, sex and age (± 5 years) at most recent TTE evaluation, and compared aortic root dimension, presence of aneurysms and tortuous arteries on imaging reports, and EHR traits between two groups (Table).
Results: Participant characteristics and clinical features are summarized in Table. Although none of the P/LP variant carriers had an aortic aneurysm on TTE, they had larger aortic root size, and were more likely to have tortuous arteries, temporomandibular dysfunction, varicose vein, movement disorders than non-carriers (Table). In a separate analysis of all individuals with TTE (1 with MFS excluded), aortic root size was larger in individuals carrying a P/LP variant in 10 genes than in non-carriers during a mean follow- up of 12.8 ±7.8 years [assessed by a mix-effects model, mean difference (95%) in z-score: 0.6 (0.18-1.02) unit].
Conclusions: None of the individuals carrying a P/LP variant in aortopathy genes had an ascending aortic aneurysm or history of aortic dissection. However, P/LP variant carriers were more likely to have clinical features related to hereditary aortopathy than non-carriers. Further work is warranted to determine the clinical implications after such incidental genomic findings returned.