Familial clustering in anomalous aortic origin of a coronary artery (AAOCA): novel genetic analyses in affected siblings
S Molossi, V Segal, H Gu, P Bibalou Mihindou, E Mizerik, B Vuocolo, B Yuan, A Sabo, R Gibbs, D Reaves-O'Neal, S Sachdeva, T Doan, S Dolgner, J Schellhaas, K Y KingAbstract
Background
Familial clustering has been demonstrated in 563 families affected by anomalous aortic origin of a coronary artery (AAOCA), including 2.5% having another first-degree family member with AAOCA. No data on genetic analysis has ever been described in AAOCA.
Purpose
We aim to evaluate the trio whole genome sequencing (WGS) of affected siblings with AAOCA.
Methods
AAOCA patients, affected siblings and parents evaluated in our institution were referred to the TMC-CZI Study Addressing Rare Disease. Informed consent was obtained and blood samples collected for trio genome sequencing. Variants were analyzed using an integrated pipeline incorporating single nucleotide variants, small insertions/deletions, and copy number variants. Beyond standard pathogenicity-based filtering using inheritance models, population frequency thresholds, in silico prediction, and phenotype-driven prioritization of cardiac and vascular genes, we also systematically evaluated variants shared among affected siblings and across families to identify potential shared genetic contributors. Family-based grouping and a focused mini-cohort analysis were performed to prioritize high-confidence variants and genes recurrent across affected individuals.
Results
A total of 12 families were referred. Two families declined participation (1 with 4 siblings affected, 1 with 2 siblings affected), 2 were lost to follow up (both with 2 siblings affected), and 2 are pending enrollment (1 with 2 siblings affected and 1 with patient and father affected). The table summarizes demographics, AAOCA subtype, surgery status and genetic findings. Analyses were completed in 5 families (2 with 3 siblings affected and 3 with 2 siblings affected) while analysis in 1 family (2 siblings affected) is pending completion. One family had a genetic mutation in the gene ZNF462, which is associated with Weiss-Kruska Syndrome, a syndrome characterized by craniofacial abnormalities but with no known association with vascular anomalies. One family had a VUS in the gene ANK2, which has been linked to neurodevelopmental disease. All other families showed no known causes of vascular anomalies or cardiac conditions, and no common variants were identified within or among families.
Conclusions
This is the first undertaking of trio WGS for sibling pairs with AAOCA. Despite comprehensive genomic analysis across multiple variant classes and inheritance models, no clear monogenic cause was identified in most families, suggesting potential genetic heterogeneity, reduced penetrance, or multifactorial mechanisms underlying familial AAOCA.