2 research outputs found
Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.
IMPORTANCE
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.
OBJECTIVE
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.
MAIN OUTCOMES AND MEASURES
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.
RESULTS
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.
CONCLUSIONS AND RELEVANCE
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.This study was supported in
part by grants PID2019-104776RB-I00 and CB16/
11/00399 (Dr de la Pompa) from the Spanish
Ministerio de Ciencia e Innovación (MCIN/ AEI/
10.13039/501100011033/); a grant from Hadassah
France Association (Drs Gilon and Tessler); a grant
from the Center for Interdisciplinary Data Science
Research of the Hebrew University of Jerusalem
(Dr Tessler); grant R35 CA220340 from the
National Institutes of Health (Dr Blacklow), and
grants R21HL150373, R01HL114823 (Dr Body); BSF
grants 2013269 and 2017245 (Drs. Sprinzak and
Blacklow); a consolidator grant from the European
Research Council (Genomia –
ERC-COG-2017-771945; Dr Loeys); the European
Reference Network on rare multisystemic vascular
disorders (VASCERN - project ID: 769036 partly
cofunded by the European Union Third Health
Programme (Drs Loeys and Verstraeten); funding
from the Outreach project (Dutch Heart
Foundation; Dr Luyckx); funding from Heart and
Stroke Foundation of Canada/Robert M Freedom
Chair of Cardiovascular Science (Dr Mital); sample
biobanking and sequencing from Canada were
supported by grants from the Leducq Foundation
Transatlantic Networks of Excellence grant, and the
Ted Rogers Centre for Heart Research; ISF grant
1053/12 (Dr Durst); and grant R01HL150401 from National Heart, Lung, and Blood Institute
(Dr Muehlschlegel).S