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.

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy.

Background: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.

Objectives: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors.

Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

Purpose: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework.

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English.

Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms.

Purpose: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

Purpose: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.

Methods: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms.

Noncompaction Cardiomyopathy, Sick Sinus Disease, and Aortic Dilatation: Too Much for a Single Diagnosis?

mutations have been reported in association with sick sinus syndrome. A more complex phenotype, including noncompaction cardiomyopathy and aortic dilatation, has recently emerged. We report 3 family members with the pathogenic p.

Direct and indirect effect of the COVID-19 pandemic on patients with cardiomyopathy.

Objectives: (1) To evaluate the prevalence and hospitalisation rate of COVID-19 infections among patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) in the Royal Brompton and Harefield Hospital Cardiovascular Research Centre (RBHH CRC) Biobank. (2) To evaluate the indirect impact of the pandemic on patients with cardiomyopathy through the Heart Hive COVID-19 study. (3) To assess the impact of the pandemic on national cardiomyopathy-related hospital admissions.

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy.

Objective: The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM.

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.

Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).

Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM.

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

Background: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.

Objectives: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.

Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals.

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection.

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.

A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy.

Purpose: We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM).

Methods: Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics.

ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure.

Background: Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects.

Methods And Results: We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus.

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues.

Next generation diagnostics in inherited arrhythmia syndromes : a comparison of two approaches.

Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR).

16p11.2-p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2.

Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.

Republished review: Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist.

The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic.

Next generation sequencing for clinical diagnostics and personalised medicine: implications for the next generation cardiologist.

The fast moving field of genomic medicine is already impacting on clinical care and cardiologists are fortunate to be in a position to benefit early from the transformative advances in genomics. However, the challenges associated with genomics in the clinic in general, and with next generation sequencing technologies in particular, are significant and cardiologists need to be prepared if they wish to surf the wave of genomic opportunity. This paper presents an overview of the implications of next generation sequencing for clinical diagnostics and personalised medicine in the cardiology clinic.

A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy.

Aims: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.