Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.

Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes.

A recurrent ACTA1 amino acid change in mosaic form causes milder asymmetric myopathy.

We describe three patients with asymmetric congenital myopathy without definite nemaline bodies and one patient with severe nemaline myopathy. In all four patients, the phenotype had been caused by pathogenic missense variants in ACTA1 leading to the same amino acid change, p.(Gly247Arg).

heterozygous pathogenic variant in an autopsy case of multiple aneurysms and right renal artery dissection: a case report.

Background: Marfan syndrome is a potentially fatal inherited autosomal dominant condition impacting the cardiovascular and the skeletal system with an estimated 25% cases caused by sporadic genetic variations. Given the genetic inheritance pattern, an autopsy of probands with Marfan syndrome-associated mortality is critical to establish the phenotypic expression and clinical implications of the particular genetic variant, especially for first-degree relatives. We present the findings of a Marfan syndrome proband decedent presenting with sudden onset abdominal pain and unexplained retroperitoneal abdominal hemorrhage.

Disruption of FBN1 by an Alu element insertion: A novel genetic cause of Marfan syndrome.

Alu elements are retrotransposons with ubiquitous presence in the human genome that have contributed to human genomic diversity and health. These approximately 300-bp sequences can cause or mediate disease by disrupting coding/splicing regions in the germline, by insertional mutagenesis in somatic cells, and in promoting formation of copy-number variants. Alu elements may also disrupt epigenetic regulation by affecting non-coding regulatory regions.

APOL1 G3 Variant Is Associated with Cardiovascular Mortality and Sudden Cardiac Death in Patients Receiving Maintenance Hemodialysis of European Ancestry.

Introduction: The G1 and G2 variants in the APOL1 gene convey high risk for the progression of chronic kidney disease in African Americans. The G3 variant in APOL1 is more common in patients of European ancestry (EA); outcomes associated with this variant have not been explored previously in EA patients receiving dialysis.

Methods: DNA was collected from approximately half of the patients enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial and genotyped for the G3 variants.

Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing.

Importance: Genetic testing can guide management of both cardiomyopathies and arrhythmias, but cost, yield, and uncertain results can be barriers to its use. It is unknown whether combined disease testing can improve diagnostic yield and clinical utility for patients with a suspected genetic cardiomyopathy or arrhythmia.

Objective: To evaluate the diagnostic yield and clinical management implications of combined cardiomyopathy and arrhythmia genetic testing through a no-charge, sponsored program for patients with a suspected genetic cardiomyopathy or arrhythmia.

Phosphorylation of Lamin A/C at serine 22 modulates Na 1.5 function.

Variants in the LMNA gene, which encodes for Lamin A/C, are associated with cardiac conduction disease (CCD). We previously reported that Lamin A/C variants p.R545H and p.

Comprehensive Genetic Testing for Pediatric Hypertrophic Cardiomyopathy Reveals Clinical Management Opportunities and Syndromic Conditions.

Hypertrophic cardiomyopathy (HCM) has historically been diagnosed phenotypically. Through genetic testing, identification of a molecular diagnosis (MolDx) is increasingly common but the impact on pediatric patients is unknown. This was a retrospective study of next-generation sequencing data for 602 pediatric patients with a clinician-reported history of HCM.

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.

Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.

Sudden Cardiac Death-A New Insight Into Potentially Fatal Genetic Markers.

Sudden cardiac death (SCD) is an unexpected and dramatic event. It draws special attention especially in young, seemingly healthy athletes. Our scientific paper is based on the death of a young, 23-year-old professional footballer, who died on the football field after a two-year history of cardiac symptoms.

Harmonizing the Collection of Clinical Data on Genetic Testing Requisition Forms to Enhance Variant Interpretation in Hypertrophic Cardiomyopathy (HCM): A Study from the ClinGen Cardiomyopathy Variant Curation Expert Panel.

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection.

Novel heterozygous truncating titin variants affecting the A-band are associated with cardiomyopathy and myopathy/muscular dystrophy.

Background: Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A-band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants.