Mitral valve prolapse: From new mechanisms to diagnostic challenges

Mitral valve prolapse (MVP) is the most common primary valvular abnormality, associated with various degrees of incompetence and sequelae, including heart failure and sudden cardiac death. Recent improvements in echocardiographic techniques and new insights into mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. Here we review the genetic etiology, clinical significance, diagnosis, and treatment options for MVP patients

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

Is Bicuspid Aortic Valve Morphology Genetically Determined? A Family-Based Study

International audienceBicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives