A systematic study of mosaicism in heritable thoracic aortic aneurysm and dissection

Mosaicisms are often overlooked in routine molecular diagnosis. Although not common, they are of great significance for accurate diagnosis and genetic counseling. In this study, we systematically evaluated the frequency of mosaicisms in both asymptomatic parents and affected patients with thoracic aortic aneurysm and dissection (TAAD). Next-generation sequencing (NGS) data from 1085 patients was reanalyzed with a more lenient allele frequency to detect potential mosaic variants. In addition, parental mosaicisms were investigated in 80 TAAD families. Finally, a total of six mosaic variants were detected in our cohort. Three of them were identified in symptomatic patients and three were in asymptomatic parents. Notably, a low-level mosaic variant in TGFB2 was detected combined with a causative FBN1 variant in patient AD2001, which might partially explain the clinical heterogeneity in his family. Our study hinted that it is necessary and feasible to implement mosaicism analysis in routine molecular diagnosis. • Mosaicism might be more common in heritable aortopathies than previously realized. • Mosaicism can be present in both symptomatic patients and asymptomatic parents. • It is necessary to implement mosaicism analysis in routine molecular diagnosis. • Amplicon-based deep sequencing is easy and effective to confirm suspected mosaicisms.