Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve
Authors: 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 
Published: July 2023

ImportanceNonsyndromic 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.ObjectiveTo identify a new gene for nsBAV.Design, Setting, and ParticipantsThis 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.Main Outcomes and MeasuresTo 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.ResultsA 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.Conclusions and RelevanceThis 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.