Application of this method to clinical variant databases demonstrated 20% of similar variants of unknown significance in splice regions affect splicing. Results: Splice-altering variants of unknown significance were enriched in DCM cases over controls and present in 2% of DCM patients (=0.002). The effects of these variants on splicing were assessed using an in vitro splice assay. Methods: Rare variants of unknown significance located in the splice regions of highly expressed exons from 203 DCM cases, 3329 normal subjects, and clinical variant databases were identified. Although variants which disrupt canonical splice signals (ie, invariant dinucleotide of splice donor site, invariant dinucleotide of the splice acceptor site) at exon-intron junctions are readily recognized as truncating variants, the effects of other nearby sequence variations on splicing and their contribution to disease is uncertain. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.īackground: Heterozygous truncating variants cause 10% to 20% of idiopathic dilated cardiomyopathy (DCM). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74 95% CI: 2.43-18.7 P < 0.001).Ĭonclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49 95% CI: 9%-32%). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69 95% confidence interval : 1.38-2.07 P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23 95% CI: 3.07-5.83 P < 0.001). Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493 1 in 407). Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Erica mazaika ware