Mansoorshahi Sara, Yetman Anji T, Bissell Malenka M, Kim Yuli Y, Michelena Hector, Hui Dawn S, Caffarelli Anthony, Andreassi Maria G, Foffa Ilenia, Guo Dongchuan, Citro Rodolfo, De Marco Margot, Tretter Justin T, Morris Shaine A, Body Simon C, Chong Jessica X, Bamshad Michael J, Milewicz Dianna M, Prakash Siddharth K
Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
Children's Hospital and Medical Center, University of Nebraska, Omaha, Nebraska.
medRxiv. 2024 Feb 8:2024.02.07.24302406. doi: 10.1101/2024.02.07.24302406.
Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of , , channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.
二叶式主动脉瓣（BAV）是最常见的成人先天性心脏病变，估计人群患病率为1%。我们假设BAV的早发并发症（EBAV）是由特定的有影响力的基因变异驱动的。我们分析了全外显子序列（WES），以确定导致215个EBAV家族中BAV疾病的罕见编码变异。111个EBAV家族（占总数的51%）中存在因果基因的预测致病变异，包括导致BAV的基因（8%）或遗传性胸主动脉疾病（HTAD，17%）。经过适当筛选后，我们还在26个与常染色体显性先天性心脏表型相关的新基因中鉴定出93个变异，包括、、通道病基因以及1型和5型胶原基因的复发性有害变异。这些发现证实了我们的假设，即独特的罕见基因变异导致了BAV疾病的早发并发症。
