Rare type I collagen variants in early-onset bicuspid aortic valve disease: Overlap with Ehlers-Danlos syndrome and osteogenesis imperfecta

Bicuspid aortic valve (BAV) is the most common congenital heart lesion in adults and is often associated with thoracic aortic aneurysms and aortic stenosis. The genetic causes of most non-syndromic cases of BAV remain unknown. Pathogenic variants in COL1A1 or COL1A2 , which encode type I collagen (COL1), cause osteogenesis imperfecta (OI), a rare disorder marked by bone fragility. Although aortic valve phenotypes, including BAV, have been described in OI, COL1 genes have not been implicated in sporadic BAV. We report rare COL1 variants in individuals with early-onset BAV (EBAV) complications. Whole-exome sequencing was performed in 272 non-syndromic BAV probands who developed valve or aortic complications before age 30 (EBAV) and 272 biological relatives. Variants were filtered by allele frequency, inheritance pattern, ClinVar classification, and in silico predictions. Participants with rare predicted damaging COL1 variants were recontacted to confirm phenotypes. Rare coding variants in COL1A1 ( n = 5) and COL1A2 ( n = 5) were identified in 10 (4%) EBAV probands, representing a 30-fold enrichment compared with European ancestry populations. Only two variants involved glycine substitutions in triple-helical domains. Affected probands presented with aortic regurgitation and/or thoracic aneurysms requiring repair and exhibited subtle connective tissue features such as joint hypermobility, recurrent fractures, or dental abnormalities. Predicted damaging COL1 variants are enriched in EBAV probands with features overlapping OI and Ehlers-Danlos syndrome, though involving different residues than those in OI. Genetic testing for these variants may help identify individuals who could benefit from personalized surveillance or targeted preventive strategies.