Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery.

Background: Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies.

Methods: We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies.

Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.

Background: One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint".

Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.

Methods: We enrolled 436 patients with HCM (median age, 60 years; 28.

Assessing the association between genetic and phenotypic features of dilated cardiomyopathy and outcome in patients with coronary artery disease.

Aims: To examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD).

Methods And Results: This study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated.

Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy.

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls.

Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis.

Methods: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht.

Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies.

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states.

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy.

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.

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.

Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: defining a healthy volunteer cohort.

The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities toward advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations, such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1000 individuals free of cardiovascular disease (CVD).

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions.

Purpose: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning variant prioritization tools are imprecise and ignore important parameters defining gene-disease relationships, e.g.

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.

Predicting oligonucleotide therapeutic efficacy at the population level.

Background: DNA-directed RNA interfering (RNAi) mediators that follow the classic Watson-Crick base pairing to bind to their molecular targets and exert their silencing capacities have been identified to be relatively insensitive to single nucleotide polymorphisms (SNPs). The experimental evaluation of a few putative genomic SNPs in a quasi-species population is the only approach scientists have been employing so far for the experimental validation of the efficacy of oligonucleotide drugs on a given population. These studies are inherently constrained by the number of SNPs that can be experimentally supported in the context of an identified molecular target.

RACE-SEQ and Population-Wide Polymorphism Susceptibility Testing for Endonucleolytically Active, RNA-Targeting Therapeutics.

High-throughput sequencing of the products of 5' RNA ligase-mediated rapid amplification of cDNA ends (5' RLM-RACE) reactions (RACE-SEQ) enables the mapping and digital enumeration of expected and novel 5' ends in RNA molecules. The resulting data are essential in documenting the mechanism of action and precision of endonucleolytically active, RNA-targeting drugs such as RNase H-active antisense or small interfering RNA. When applied to error-prone replication systems such as RNA viruses or in vitro RNA replicon systems, the method can additionally report the relative susceptibility of known and unknown polymorphisms to a prospective sequence-specific drug, making it a powerful tool in patient selection and stratification as well as resistance prediction.

Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs.

Low allelic and clonal variability among endogenous RNAi targets has focused mismatch tolerance studies to RNAi-active guide strands. However, the inherent genomic instability of RNA viruses such as hepatitis C virus (HCV) gives rise to quasi-species mutants within discrete clones: this facilitates mismatch tolerance studies from a target perspective. We recently quantified the slicing imprecision of Argonaute 2 using small interfering RNA (siRNA) analogs of the DNA-directed RNAi drug TT-034 and next-generation sequencing of 5' RNA ligase-mediated rapid amplification of cDNA ends (RACE-SEQ).