Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes.

Background: Friedreich's ataxia (FRDA) is an autosomal recessive disease, whereby homozygous inheritance of an expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene leads to transcriptional repression of the encoded protein frataxin. FRDA is a progressive neurodegenerative disorder, but the primary cause of death is heart disease which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them fully explain why its deficiency causes the FRDA phenotypes nor why the most affected cell types are neurons and cardiomyocytes.

Corrigendum: Phenotypic variability in iPSC-induced cardiomyocytes and cardiac fibroblasts carrying diverse mutations.

[This corrects the article DOI: 10.3389/fphys.2021.

Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse Mutations.

Mutations in the gene (encoding lamin A/C) are a significant cause of familial arrhythmogenic cardiomyopathy. Although the penetrance is high, there is considerable phenotypic variability in disease onset, rate of progression, arrhythmias, and severity of myopathy. To begin to address whether this variability stems from specific mutation sites and types, we generated seven patient-specific induced pluripotent stem cell (iPSC) lines with various mutations.

The dynamin-related protein 1 is decreased and the mitochondrial network is altered in Friedreich's ataxia cardiomyopathy.

Friedreich ataxia is an autosomal recessive congenital neurodegenerative disease caused by a deficiency in the frataxin protein and is often diagnosed in young adulthood. An expansion of guanine-adenine-adenine repeats in the first intron of the FXN gene leads to decreased frataxin expression. Frataxin plays an essential role in mitochondrial metabolism.

Generation of a heterozygous FLNC mutation-carrying human iPSC line, USFi002-A, for modeling dilated cardiomyopathy.

Dilated Cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in different genes including TTN, MYH7, and LMNA, have been linked to the development of DCM. Here, we generated a human induced pluripotent stem cell (IPSC) line from a DCM patient with a familial history that carries a frameshift mutation in Filamin C (FLNC).

Establishment of an arrhythmogenic right ventricular cardiomyopathy derived iPSC cell line (USFi004-A) carrying a heterozygous mutation in PKP2 (c.1799delA).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant inherited disease, with variable penetrance and expressivity. Currently, more than 14 different genetic loci have been reported for ARVC, the majority being desmosomal genes like Plakophilin-2 (PKP2). Here, we generated an iPSC cell line bearing a pathogenic heterozygous mutation in PKP2 (c.

Generation of a Friedreich's Ataxia patient-derived iPSC line USFi001-A.

Friedreich's Ataxia (FA) is an autosomal recessive disorder with an incidence of 1 in 50,000 in Caucasians. Most cases are caused by a biallelic GAA expansion in the first intron of the Frataxin (FXN) gene. FA is a neurodegenerative disease, but the leading cause of death is hypertrophic cardiomyopathy (HCM) that develops in 60% of the patients.

Generation of an iPSC cell line (USFi003-A) from a patient with dilated cardiomyopathy carrying a heterozygous mutation in LMNA (p.R541C).

Mutations in the gene that encodes the nuclear envelope proteins lamin A/C (LMNA) are considered to be a prominent cause of Dilated cardiomyopathy (DCM), a leading cause of heart failure and a prevalent indication for heart transplant. Here we described the generation of induced pluripotent stem cells (iPSCs) from a 53-year-old female with DCM plus progressive conduction disease who carry a heterozygous mutation in LMNA (c.1621C > T, p.

Functional testing for variant prioritization in a family with long QT syndrome.

Next-generation sequencing platforms are being increasingly applied in clinical genetic settings for evaluation of families with suspected heritable disease. These platforms potentially improve the diagnostic yield beyond that of disease-specific targeted gene panels, but also increase the number of rare or novel genetic variants that may confound precise diagnostics. Here, we describe a functional testing approach used to interpret the results of whole exome sequencing (WES) in a family presenting with syncope and sudden death.

The NYCKidSeq project: study protocol for a randomized controlled trial incorporating genomics into the clinical care of diverse New York City children.

Background: Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing.

In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems.

The usage of flavored electronic nicotine delivery systems (ENDS) is popular, specifically in the teen and young adult age-groups. The possible cardiac toxicity of the flavoring aspect of ENDS is largely unknown. Vaping, a form of electronic nicotine delivery, uses "e-liquid" to generate "e-vapor," an aerosolized mixture of nicotine and/or flavors.

Physical and functional interaction sites in cytoplasmic domains of KCNQ1 and KCNE1 channel subunits.

The cardiac potassium current is carried by a channel complex formed from α-subunits encoded by KCNQ1 and β-subunits encoded by KCNE1. Deleterious mutations in either gene are associated with hereditary long QT syndrome. Interactions between the transmembrane domains of the α- and β-subunits determine the activation kinetics of .

Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series.

Our aim is to characterize predicted protein-truncating variants (PTVs) in MYBPC3, the gene most commonly associated with hypertrophic cardiomyopathy (HCM), found in a series of autopsied HCM cases after sudden unexpected cardiac death. All cases underwent death scene investigation, gross and microscopic autopsies, toxicological testing, a review of medical records, and a molecular analysis of 95 cardiac genes. We found four pathogenic PTVs in MYBPC3 among male decedents.

Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes.

Background: Deleterious mutations in KCNQ1 may lead to an autosomal dominant form of long QT syndrome (LQTS) (Romano-Ward) or autosomal recessive form (Jervell and Lange-Nielsen). Both are associated with severe ventricular tachyarrhythmias due to the reduction of the slowly activating delayed rectifier K current (I). Our objective was to investigate the functional consequences of KCNQ1-R562S mutation in an atypical form of KCNQ1-linked LQTS.

Synonymous nucleotide modification of the gene affects both mRNA characteristics and translation of the encoded hERG ion channel.

Synonymous nucleotide variation is increasingly recognized as a factor than can affect protein expression, but the underlying mechanisms are incompletely understood. Here, we investigated whether synonymous changes could affect expression of the potassium voltage-gated channel subfamily H member 2 () gene, encoding the human ether-a-go-go-related gene (hERG) ion channel, which is linked to hereditary cardiac arrhythmia. We examined a previously described synthetic version (hERG-codon modified (CM)) with synonymous substitutions designed to reduce GC content, rare codons, and mRNA secondary structure relative to the native construct (hERG-NT).

Functional Assays to Screen and Dissect Genomic Hits: Doubling Down on the National Investment in Genomic Research.

The National Institutes of Health have made substantial investments in genomic studies and technologies to identify DNA sequence variants associated with human disease phenotypes. The National Heart, Lung, and Blood Institute has been at the forefront of these commitments to ascertain genetic variation associated with heart, lung, blood, and sleep diseases and related clinical traits. Genome-wide association studies, exome- and genome-sequencing studies, and exome-genotyping studies of the National Heart, Lung, and Blood Institute-funded epidemiological and clinical case-control studies are identifying large numbers of genetic variants associated with heart, lung, blood, and sleep phenotypes.

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Background: Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office.

Methods And Results: The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years).

Compound heterozygous CASQ2 mutations and long-term course of catecholaminergic polymorphic ventricular tachycardia.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac disorder characterized by episodic ventricular tachycardia during adrenergic stimulation. It is associated with significant morbidity and mortality. Knowledge of the underlying genetic cause, pathogenesis, and the natural history of the disease remains incomplete.

Express with caution: Epitope tags and cDNA variants effects on hERG channel trafficking, half-life and function.

Introduction: Genetic mutations in KCNH2, which encodes hERG, the alpha subunit of the potassium channel responsible for the I current, cause long QT syndrome (LQTS), an inherited cardiac arrhythmia disorder. Electrophysiology techniques are used to correlate genotype with molecular phenotype to determine which mutations identified in patients diagnosed with LQTS are disease causing, and which are benign. These investigations are usually done using heterologous expression in cell lines, and often, epitope fusion tags are used to enable isolation and identification of the protein of interest.