Devyn Mitchell
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View article: Patient-derived Cellular Models of Polygenic Scores: Application to Long QT Syndrome
Patient-derived Cellular Models of Polygenic Scores: Application to Long QT Syndrome Open
Polygenic scores (PGS) have emerged as important modifiers of disease risk, drug response, and rare variant penetrance, but the biological mechanisms underlying these associations remain poorly understood. To experimentally investigate the…
View article: Structural Evaluation of<i>RYR2</i>-CPVT Missense Variants and Continuous Bayesian Estimates of their Penetrance
Structural Evaluation of<i>RYR2</i>-CPVT Missense Variants and Continuous Bayesian Estimates of their Penetrance Open
Background Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is strongly associated with rare missense variants in RYR2 , the gene encoding the intracellular calcium release channel RyR2. Precision medicine is complicated by inc…
View article: Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval
Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval Open
Long QT syndrome (LQTS), an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions, represents a significant clinical challenge due to its complex genetic underp…
View article: EFP Analyzer: A fast, accurate, and easy-to-teach program for analyzing Extracellular Field Potentials from iPSC-derived cardiomyocytes
EFP Analyzer: A fast, accurate, and easy-to-teach program for analyzing Extracellular Field Potentials from iPSC-derived cardiomyocytes Open
Rationale Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an emerging model for determining drug effects and modeling disease. Specialized devices can generate Extracellular Field Potential (EFP) measurements from these…
View article: Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve <i>KCNH2</i> -LQTS Variant Classification and Cardiac Event Risk Stratification
Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve <i>KCNH2</i> -LQTS Variant Classification and Cardiac Event Risk Stratification Open
BACKGROUND: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Mo…
View article: Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve<i>KCNH2</i>-LQTS Variant Classification and Cardiac Event Risk Stratification
Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve<i>KCNH2</i>-LQTS Variant Classification and Cardiac Event Risk Stratification Open
Background Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often owing to lack of functional data…
View article: Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval
Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval Open
Long QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome with congenital and drug-induced presentations and known monogenic and polygenic contributions. LQTS represents a significant clinical challenge due to its complex genetic…
View article: Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies
Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies Open
Background: Rare protein-altering variants in SCN5A , KCNQ1 , and KCNH2 are major causes of Brugada syndrome and the congenital long QT syndrome. While splice-altering variants lying outside 2-bp canonical splice sites can cause these dise…
View article: Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies
Functional Assays Reclassify Suspected Splice-Altering Variants of Uncertain Significance in Mendelian Channelopathies Open
Background Rare protein-altering variants in SCN5A, KCNQ1 , and KCNH2 are major causes of Brugada Syndrome (BrS) and the congenital Long QT Syndrome (LQTS). While splice-altering variants lying outside 2-bp canonical splice sites can cause…
View article: Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study
Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study Open
Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are…
View article: A Massively Parallel Trafficking Assay Accurately Predicts Loss of Channel Function in<i>KCNH2</i>Variants
A Massively Parallel Trafficking Assay Accurately Predicts Loss of Channel Function in<i>KCNH2</i>Variants Open
High throughput genomics has greatly facilitated identification of genetic variants. However, determining which variants contribute to disease causation is challenging with more than half of all missense variants now classified as variants…
View article: Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study
Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study Open
In 21,846 eMERGE-III participants, sequencing 10 arrhythmia syndrome disease genes identified 123 individuals with pathogenic or likely pathogenic (P/LP) variants. Compared to non-carriers, P/LP carriers had a significantly higher burden o…