Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Background Familial Hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in one of three genes. In the 60% of patients who are mutation-negative we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL-C-raising alleles using a 12-SNP score. The aims of the study were to improve the selection of SNPs, and to replicate the results in additional samples. Methods Receiver-operating characteristic curves were used to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from six countries for six LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from an UK population sample (WHII). Results Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, while sequential removal of SNPs with smaller effects/lower frequency showed a weighted score of six SNPs performed as well as the 12-SNP score. Meta-analysis of the weighted 6-SNP score, based on polymorphisms in CELSR2, APOB, ABCG5/8, LDLR and APOE loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P<2.2×10-16). Modeling in individuals with a 6-SNP score in the top three quarters of the score distribution, indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. Conclusion A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy subjects. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

SUMMARYMitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals1–3. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery4,5. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds) that segregates with MVP in the family. Morpholino knockdown of the zebrafish homolog dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 mRNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells, and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs as well as in Dchs1+/− mouse MVICs result in altered migration and cellular patterning, supporting these processes as etiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.