Tessler Idit, Albuisson Juliette, Piñeiro-Sabarís Rebeca, Verstraeten Aline, Kamber Kaya Hatem Elif, Siguero-Álvarez Marcos, Goudot Guillaume, MacGrogan Donal, Luyckx Ilse, Shpitzen Shoshana, Levin Galina, Kelman Guy, Reshef Noga, Mananet Hugo, Holdcraft Jake, Muehlschlegel Jochen D, Peloso Gina M, Oppenheim Olya, Cheng Charles, Mazzella Jean-Michael, Andelfinger Gregor, Mital Seema, Eriksson Per, Billon Clarisse, Heydarpour Mahyar, Dietz Harry C, Jeunemaitre Xavier, Leitersdorf Eran, Sprinzak David, Blacklow Stephen C, Body Simon C, Carmi Shai, Loeys Bart, de la Pompa José Luis, Gilon Dan, Messas Emmanuel, Durst Ronen
Cardiology Department, Hadassah Medical Center, Jerusalem, Israel.
Sheba Medical Center, Ramat Gan, Israel.
JAMA Cardiol. 2023 Aug 1;8(8):721-731. doi: 10.1001/jamacardio.2023.1469.
Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine.
To identify a new gene for nsBAV.
DESIGN, SETTING, AND PARTICIPANTS: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US.
To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV.
A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background.
This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.
非综合征性二叶式主动脉瓣（nsBAV）是最常见的先天性心脏瓣膜畸形。二叶式主动脉瓣具有遗传因素，但仅鉴定出少数致病基因；了解二叶式主动脉瓣的遗传学是开发个性化医疗的关键所在。
鉴定一种新的nsBAV基因。
设计、设置和参与者：这是一项全面的多中心遗传关联研究，基于家族队列中的候选基因优先排序，随后在复制队列中进行罕见和常见关联研究。使用体内小鼠模型进行进一步验证。研究数据于2019年10月至2022年10月进行分析。该研究纳入了三组二叶式主动脉瓣患者：（1）发现队列是来自29个法国和以色列血统家系的大量遗传性病例队列；（２）针对罕见变异的复制队列1包括来自不同欧洲血统的散发性无关病例；（３）复制队列2是针对来自欧洲和美国的散发性无关病例中常见变异的第二个验证队列。
通过分析家族病例外显子组测序和基因优先排序工具来鉴定nsBAV的候选基因。在复制队列1中搜索罕见且预测有害的变异以及遗传关联。复制队列2用于研究常见变异与二叶式主动脉瓣的关联。
本研究共纳入938例二叶式主动脉瓣患者：发现队列中有69例（占7.4%），复制队列1中有417例（占44.5%），复制队列2中有452例（占48.2%）。鉴定出一种新的人类nsBAV基因，即Mindbomb1同源物MIB (1)。Mindbomb1同源物（MIB1）是一种E3泛素连接酶，对心脏发育过程中的NOTCH信号激活至关重要。在发现队列和复制队列1中约2%的nsBAV索引病例中，检测到罕见的MIB1变异，预测具有损害性，与基于人群的对照相比显著富集（2%的病例对0.9%的对照；P = 0.03）。在复制队列2中，鉴定出与nsBAV显著相关的MIB1风险单倍型（置换检验，重复1000次；P = 0.02）。在我们的队列中鉴定出的携带Mib1变异的两种基因工程小鼠模型在NOTCH1敏感的遗传背景下表现出二叶式主动脉瓣。
这项遗传关联研究确定MIB1基因与nsBAV相关联。这突出了NOTCH通路在二叶式主动脉瓣病理生理学中的关键作用及其作为未来诊断和治疗干预靶点的潜力。
