Browsing by Author "Landstrom, Andrew P"
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Item Open Access A 14-year-old in heart failure with multiple cardiomyopathy variants illustrates a role for signal-to-noise analysis in gene test re-interpretation.(Clinical case reports, 2019-01) Connell, Patrick S; Jeewa, Aamir; Kearney, Debra L; Tunuguntla, Hari; Denfield, Susan W; Allen, Hugh D; Landstrom, Andrew PVariants of unknown significance in cardiomyopathic disease should be analyzed systematically based on the prevalence of the variant in the population compared to prevalence of disease, evidence that other variants in the gene are pathologic, consistency of prediction software on pathogenicity, and the current clinical consensus.Item Open Access A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C.(Journal of muscle research and cell motility, 2020-11-11) Reinoso, Tyler R; Landim-Vieira, Maicon; Shi, Yun; Johnston, Jamie R; Chase, P Bryant; Parvatiyar, Michelle S; Landstrom, Andrew P; Pinto, Jose R; Tadros, Hanna JFamilial cardiomyopathy is an inherited disease that affects the structure and function of heart muscle and has an extreme range of phenotypes. Among the millions of affected individuals, patients with hypertrophic (HCM), dilated (DCM), or left ventricular non-compaction (LVNC) cardiomyopathy can experience morphologic changes of the heart which lead to sudden death in the most detrimental cases. TNNC1, the gene that codes for cardiac troponin C (cTnC), is a sarcomere gene associated with cardiomyopathies in which probands exhibit young age of presentation and high death, transplant or ventricular fibrillation events relative to TNNT2 and TNNI3 probands. Using GnomAD, ClinVar, UniProt and PhosphoSitePlus databases and published literature, an extensive list to date of identified genetic variants in TNNC1 and post-translational modifications (PTMs) in cTnC was compiled. Additionally, a recent cryo-EM structure of the cardiac thin filament regulatory unit was used to localize each functionally studied amino acid variant and each PTM (acetylation, glycation, s-nitrosylation, phosphorylation) in the structure of cTnC. TNNC1 has a large number of variants (> 100) relative to other genes of the same transcript size. Surprisingly, the mapped variant amino acids and PTMs are distributed throughout the cTnC structure. While many cardiomyopathy-associated variants are localized in α-helical regions of cTnC, this was not statistically significant χ2 (p = 0.72). Exploring the variants in TNNC1 and PTMs of cTnC in the contexts of cardiomyopathy association, physiological modulation and potential non-canonical roles provides insights into the normal function of cTnC along with the many facets of TNNC1 as a cardiomyopathic gene.Item Open Access Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.(Circulation. Genomic and precision medicine, 2021-02) Connell, Patrick S; Berkman, Amy M; Souder, BriAnna M; Pirozzi, Elisa J; Lovin, Julia J; Rosenfeld, Jill A; Liu, Pengfei; Tunuguntla, Hari; Allen, Hugh D; Denfield, Susan W; Kim, Jeffrey J; Landstrom, Andrew PBackground
TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing.Methods
Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed.Results
Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance.Conclusions
Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.Item Open Access Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise.(Heart rhythm, 2018-07) Landstrom, Andrew P; Fernandez, Ernesto; Rosenfeld, Jill A; Yang, Yaping; Dailey-Schwartz, Andrew L; Miyake, Christina Y; Allen, Hugh D; Penny, Daniel J; Kim, Jeffrey JBACKGROUND:Due to rapid expansion of clinical genetic testing, an increasing number of genetic variants of undetermined significance and unclear diagnostic value are being identified in children. Variants found in genes associated with heritable channelopathies, such as long QT syndrome (LQTS), are particularly difficult to interpret given the risk of sudden cardiac death associated with pathologic mutations. OBJECTIVE:The purpose of this study was to determine whether variants in LQTS-associated genes from whole exome sequencing (WES) represent disease-associated biomarkers or background genetic "noise." METHODS:WES variants from Baylor Genetics Laboratories were obtained for 17 LQTS-associated genes. Rare variants from healthy controls were obtained from the GnomAD database. LQTS case variants were extracted from the literature. Amino acid-level mapping and signal-to-noise calculations were conducted. Clinical history and diagnostic studies were analyzed for WES subjects evaluated at our institution. RESULTS:Variants in LQTS case-associated genes were present in 38.3% of 7244 WES probands. There was a similar frequency of variants in the WES and healthy cohorts for LQTS1-3 (11.2% and 12.9%, respectively) and LQTS4-17 (27.1% and 38.4%, respectively). WES variants preferentially localized to amino acids altered in control individuals compared to cases. Based on amino acid-level analysis, WES-identified variants are indistinguishable from healthy background variation, whereas LQTS1 and 2 case-identified variants localized to clear pathologic "hotspots." No individuals who underwent clinical evaluation had clinical suspicion for LQTS. CONCLUSION:The prevalence of incidentally identified LQTS-associated variants is ∼38% among WES tests. These variants most likely represent benign healthy background genetic variation rather than disease-associated mutations.Item Open Access An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.(Circulation, 2020-02) Roberts, Jason D; Asaki, S Yukiko; Mazzanti, Andrea; Bos, J Martijn; Tuleta, Izabela; Muir, Alison R; Crotti, Lia; Krahn, Andrew D; Kutyifa, Valentina; Shoemaker, M Benjamin; Johnsrude, Christopher L; Aiba, Takeshi; Marcondes, Luciana; Baban, Anwar; Udupa, Sharmila; Dechert, Brynn; Fischbach, Peter; Knight, Linda M; Vittinghoff, Eric; Kukavica, Deni; Stallmeyer, Birgit; Giudicessi, John R; Spazzolini, Carla; Shimamoto, Keiko; Tadros, Rafik; Cadrin-Tourigny, Julia; Duff, Henry J; Simpson, Christopher S; Roston, Thomas M; Wijeyeratne, Yanushi D; El Hajjaji, Imane; Yousif, Maisoon D; Gula, Lorne J; Leong-Sit, Peter; Chavali, Nikhil; Landstrom, Andrew P; Marcus, Gregory M; Dittmann, Sven; Wilde, Arthur AM; Behr, Elijah R; Tfelt-Hansen, Jacob; Scheinman, Melvin M; Perez, Marco V; Kaski, Juan Pablo; Gow, Robert M; Drago, Fabrizio; Aziz, Peter F; Abrams, Dominic J; Gollob, Michael H; Skinner, Jonathan R; Shimizu, Wataru; Kaufman, Elizabeth S; Roden, Dan M; Zareba, Wojciech; Schwartz, Peter J; Schulze-Bahr, Eric; Etheridge, Susan P; Priori, Silvia G; Ackerman, Michael JBACKGROUND:Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS:Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS:A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS:The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.Item Open Access Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.(Scientific reports, 2019-06-21) Jones, Edward G; Mazaheri, Neda; Maroofian, Reza; Zamani, Mina; Seifi, Tahereh; Sedaghat, Alireza; Shariati, Gholamreza; Jamshidi, Yalda; Allen, Hugh D; Wehrens, Xander HT; Galehdari, Hamid; Landstrom, Andrew PJunctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.Item Open Access Association of Wolff-Parkinson-White With Left Ventricular Noncompaction Cardiomyopathy in Children.(Journal of cardiac failure, 2019-12) Howard, Taylor S; Valdes, Santiago O; Hope, Kyle D; Morris, Shaine A; Landstrom, Andrew P; Schneider, Andrew E; Miyake, Christina Y; Denfield, Susan W; Pignatelli, Ricardo H; Wang, Yunfei; Kim, Jeffrey JBACKGROUND:Wolff-Parkinson-White (WPW) has been associated with left ventricular noncompaction (LVNC) in children. Little is known about the prevalence of this association, clinical outcomes, and treatment options. METHODS:Retrospective review of subjects with LVNC. LVNC was defined by established criteria; those with congenital heart disease were excluded. Electrocardiograms (ECGs) were reviewed for presence of pre-excitation. Outcomes were compared between those with isolated LVNC and those with WPW and LVNC. RESULTS:A total of 348 patients with LVNC were identified. Thirty-eight (11%) were found to have WPW pattern on ECG, and 84% of those with WPW and LVNC had cardiac dysfunction. In Kaplan-Meier analysis, there was significantly lower freedom from significant dysfunction (ejection fraction ≤ 40%) among those with WPW and LVNC (P < .001). Further analysis showed a higher risk of developing significant dysfunction in patients with WPW and LVNC versus LVNC alone (hazard ratio 4.64 [2.79, 9.90]). Twelve patients underwent an ablation procedure with an acute success rate of 83%. Four patients with cardiac dysfunction were successfully ablated, 3 having improvement in function. CONCLUSION:WPW is common among children with LVNC and is associated with cardiac dysfunction. Ablation therapy can be safely and effectively performed and may result in improvement in function.Item Open Access Cardiac dysregulation following intrahippocampal kainate-induced status epilepticus.(Scientific reports, 2020-03-04) Levine, Amber T; Born, Heather A; Landstrom, Andrew P; Larson, Samuel; Lee, Wai Ling; Dao, An T; Wehrens, Xander H; Lai, Yi-Chen; Anderson, Anne EStatus epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) are observed in patients following SE. We characterized ictal (during a seizure) and interictal (between seizure) cardiac arrhythmogenesis following SE using continuous electrocardiography and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy. We quantified heart rhythm abnormalities and examined whether the frequency of cardiac events correlated with epileptiform activity, circadian (light/dark) cycle, the presence of seizures, and survival during this period of early epileptogenesis (the development of epilepsy) following SE. Shortly following SE, mice developed an increased interictal heart rate and heart rhythm abnormalities (i.e. sinus pause and sinus arrhythmias) when compared to control mice. Heart rhythm abnormalities were more frequent during the light cycle and were not correlated with increased epileptiform activity or seizure frequency. Finally, SE animals had early mortality, and a death event captured during vEEG recording demonstrated severe bradycardia prior to death. These cardiac changes occurred within 14 days after SE and may represent an early risk factor for sudden death following SE.Item Open Access Copy Number Variants of Undetermined Significance Are Not Associated with Worse Clinical Outcomes in Hypoplastic Left Heart Syndrome.(The Journal of pediatrics, 2018-11) Dailey-Schwartz, Andrew L; Tadros, Hanna J; Azamian, Mahshid Sababi; Lalani, Seema R; Morris, Shaine A; Allen, Hugh D; Kim, Jeffrey J; Landstrom, Andrew POBJECTIVE:To determine the prevalence, spectrum, and prognostic significance of copy number variants of undetermined significance (cnVUS) seen on chromosomal microarray (CMA) in neonates with hypoplastic left heart syndrome (HLHS). STUDY DESIGN:Neonates with HLHS who presented to Texas Children's Hospital between June 2008 and December 2016 were identified. CMA results were abstracted and compared against copy number variations (CNVs) in ostensibly healthy individuals gathered from the literature. Findings were classified as normal, consistent with a known genetic disorder, or cnVUS. Survival was then compared using Kaplan-Meier analysis. Secondary outcomes included tracheostomy, feeding tube at discharge, cardiac arrest, and extracorporeal membrane oxygenation (ECMO). RESULTS:Our study cohort comprised 105 neonates with HLHS, including 70 (66.7%) with normal CMA results, 9 (8.6%) with findings consistent with a known genetic disorder, and 26 (24.7%) with a cnVUS. Six of the 26 (23.0%) neonates with a cnVUS had a variant that localized to a specific region of the genome seen in the healthy control population. One-year survival was 84.0% in patients with a cnVUS, 68.3% in those with normal CMA results, and 33.3% in those with a known genetic disorder (P = .003). There were no significant differences in secondary outcomes among the groups, although notably ECMO was used in 15.7% of patients with normal CMA and was not used in those with cnVUS and abnormal results (P = .038). CONCLUSIONS:Among children with HLHS, cnVUSs detected on CMA are common. The cnVUSs do not localize to specific regions of the genome, and are not associated with worse outcomes compared with normal CMA results.Item Open Access Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.(Journal of visualized experiments : JoVE, 2019-01-16) Jones, Edward G; Landstrom, Andrew PAdvancements in the cost and speed of next generation genetic sequencing have generated an explosion of clinical whole exome and whole genome testing. While this has led to increased identification of likely pathogenic mutations associated with genetic syndromes, it has also dramatically increased the number of incidentally found genetic variants of unknown significance (VUS). Determining the clinical significance of these variants is a major challenge for both scientists and clinicians. An approach to assist in determining the likelihood of pathogenicity is signal-to-noise analysis at the protein sequence level. This protocol describes a method for amino acid-level signal-to-noise analysis that leverages variant frequency at each amino acid position of the protein with known protein topology to identify areas of the primary sequence with elevated likelihood of pathologic variation (relative to population "background" variation). This method can identify amino acid residue location "hotspots" of high pathologic signal, which can be used to refine the diagnostic weight of VUSs such as those identified by next generation genetic testing.Item Open Access Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening.(Molecular genetics and metabolism, 2022-03) Huggins, Erin; Holland, Maggie; Case, Laura E; Blount, Janet; Landstrom, Andrew P; Jones, Harrison N; Kishnani, Priya SPurpose
Thoroughly phenotype children with late-onset Pompe disease (LOPD) diagnosed via newborn screening (NBS) to provide guidance for long-term follow up.Methods
Twenty infants ages 6-21 months with LOPD diagnosed by NBS underwent systematic clinical evaluation at Duke University including cardiac imaging, biomarker testing, physical therapy evaluation, and speech-language pathology evaluation.Results
Of the 20 infants, four were homozygous for the "late-onset" IVS1 splice site variant c.-32-13 T > G, fourteen were compound heterozygous, and two did not have any copies of this variant. None of the patients had evidence of cardiomyopathy or cardiac rhythm disturbances. Biomarker testing showed an increase in CK, AST, and ALT in 8 patients (40%) and increase in Glc4 in two patients (10%). All patients demonstrated postural and kinematic concerns. Three patients (17%) scored below the 10%ile on the Alberta Infant Motor Scale (AIMS) and 15 patients (83%) scored above the 10%ile. Speech-language pathology assessments were normal in all patients and mild feeding/swallowing abnormalities were noted in nine patients (45%).Conclusion
Our data show high variability among children with LOPD diagnosed via NBS. Careful physical therapy evaluation is necessary to monitor for subtle musculoskeletal signs that may reflect early muscle involvement. Patients should be monitored closely for symptom progression.Item Open Access Early experience with intravenous sotalol in children with and without congenital heart disease.(Heart rhythm, 2018-12) Valdés, Santiago O; Miyake, Christina Y; Niu, Mary C; de la Uz, Caridad M; Asaki, S Yukiko; Landstrom, Andrew P; Schneider, Andrew E; Rusin, Craig G; Patel, Raajen; Lam, Wilson W; Kim, Jeffrey JBACKGROUND:Arrhythmias are common in the pediatric population. In patients unable to take oral medications or in need of acute therapy, options of intravenous (IV) antiarrhythmic medications are limited. Recently IV sotalol has become readily available, but experience in children is limited. OBJECTIVE:The purpose of this study was to describe our initial experience with the use of IV sotalol in the pediatric population. METHODS:A retrospective study of all pediatric patients receiving IV sotalol was performed. Patient demographic characteristics, presence of congenital heart disease, arrhythmia type, efficacy of IV sotalol use, and adverse effects were evaluated. RESULTS:A total of 47 patients (26 (55%) male and 24 (51%) with congenital heart disease) received IV sotalol at a median age of 2.05 years (interquartile range 0.07-10.03 years) and a median weight of 12.8 kg (interquartile range 3.8-34.2 kg), and 13 (28%) received IV sotalol in the acute postoperative setting. Supraventricular arrhythmias occurred in 40 patients (85%) and ventricular tachycardia in 7 (15%). Among 24 patients receiving IV sotalol for an active arrhythmia, acute termination was achieved in 21 (88%). Twenty-three patients received IV sotalol as maintenance therapy for recurrent arrhythmias owing to inability to take oral antiarrhythmic medications; 19 (83%) were controlled with sotalol monotherapy. No patient required discontinuation of IV sotalol secondary to adverse effects, proarrhythmia, or QT prolongation. CONCLUSION:IV sotalol is an effective antiarrhythmic option for pediatric patients and may be an excellent agent for acute termination of active arrhythmias. It was well tolerated, with no patient requiring discontinuation secondary to adverse effects.Item Open Access Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.(Journal of cellular and molecular medicine, 2021-06-10) Word, Tarah A; Quick, Ann P; Miyake, Christina Y; Shak, Mayra K; Pan, Xiaolu; Kim, Jean J; Allen, Hugh D; Sibrian-Vazquez, Martha; Strongin, Robert M; Landstrom, Andrew P; Wehrens, Xander HTCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca2+ ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca2+ handling and arrhythmic events in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg-176-Glu (R176Q) and a mutation-negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC-CMs were derived using the StemdiffTM kit. Confocal Ca2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC-CMs harbouring the R176Q variant demonstrated spontaneous SR Ca2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC50 = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca2+ handling in control iPSC-CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca2+ handling and suppresses arrhythmogenic activity in iPSC-CMs derived from a CPVT patient. Hence, this study confirms that this RyR2-inhibitor represents a promising therapeutic candidate for treatment of CPVT.Item Open Access Essential roles of the dystrophin-glycoprotein complex in different cardiac pathologies.(Advances in medical sciences, 2020-12-30) Valera, Isela C; Wacker, Amanda L; Hwang, Hyun Seok; Holmes, Christina; Laitano, Orlando; Landstrom, Andrew P; Parvatiyar, Michelle SThe dystrophin-glycoprotein complex (DGC), situated at the sarcolemma dynamically remodels during cardiac disease. This review examines DGC remodeling as a common denominator in diseases affecting heart function and health. Dystrophin and the DGC serve as broad cytoskeletal integrators that are critical for maintaining stability of muscle membranes. The presence of pathogenic variants in genes encoding proteins of the DGC can cause absence of the protein and/or alterations in other complex members leading to muscular dystrophies. Targeted studies have allowed the individual functions of affected proteins to be defined. The DGC has demonstrated its dynamic function, remodeling under a number of conditions that stress the heart. Beyond genetic causes, pathogenic processes also impinge on the DGC, causing alterations in the abundance of dystrophin and associated proteins during cardiac insult such as ischemia-reperfusion injury, mechanical unloading, and myocarditis. When considering new therapeutic strategies, it is important to assess DGC remodeling as a common factor in various heart diseases. The DGC connects the internal F-actin-based cytoskeleton to laminin-211 of the extracellular space, playing an important role in the transmission of mechanical force to the extracellular matrix. The essential functions of dystrophin and the DGC have been long recognized. DGC based therapeutic approaches have been primarily focused on muscular dystrophies, however it may be a beneficial target in a number of disorders that affect the heart. This review provides an account of what we now know, and discusses how this knowledge can benefit persistent health conditions in the clinic.Item Open Access Genetic Etiology of Left-Sided Obstructive Heart Lesions: A Story in Development.(Journal of the American Heart Association, 2021-01-12) Parker, Lauren E; Landstrom, Andrew PCongenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left-sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic valve, coarctation of the aorta, and interrupted aortic arch. These defects can arise in isolation or as a component of a defined syndrome; however, nonsyndromic defects are often observed in multiple family members and associated with high sibling recurrence risk. This clear evidence for a heritable basis has driven a lengthy search for disease-causing variants that has uncovered both rare and common variants in genes that, when perturbed in cardiac development, can result in LSOLs. Despite advancements in genetic sequencing platforms and broadening use of exome sequencing, the currently accepted LSOL-associated genes explain only 10% to 20% of patients. Further, the combinatorial effects of common and rare variants as a cause of LSOLs are emerging. In this review, we highlight the genes and variants associated with the different LSOLs and discuss the strengths and weaknesses of the present genetic associations. Furthermore, we discuss the research avenues needed to bridge the gaps in our current understanding of the genetic basis of nonsyndromic congenital heart disease.Item Open Access Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association.(Circulation. Genomic and precision medicine, 2020-08) Musunuru, Kiran; Hershberger, Ray E; Day, Sharlene M; Klinedinst, N Jennifer; Landstrom, Andrew P; Parikh, Victoria N; Prakash, Siddharth; Semsarian, Christopher; Sturm, Amy C; American Heart Association Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and Council on Clinical CardiologyAdvances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.Item Open Access Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.(JACC. Clinical electrophysiology, 2020-11) Moore, Jeremy P; Gallotti, Roberto G; Shannon, Kevin M; Bos, J Martijn; Sadeghi, Elham; Strasburger, Janette F; Wakai, Ronald T; Horigome, Hitoshi; Clur, Sally-Ann; Hill, Allison C; Shah, Maully J; Behere, Shashank; Sarquella-Brugada, Georgia; Czosek, Richard; Etheridge, Susan P; Fischbach, Peter; Kannankeril, Prince J; Motonaga, Kara; Landstrom, Andrew P; Williams, Matthew; Patel, Akash; Dagradi, Federica; Tan, Reina B; Stephenson, Elizabeth; Krishna, Mani Ram; Miyake, Christina Y; Lee, Michelle E; Sanatani, Shubhayan; Balaji, Seshadri; Young, Ming-Lon; Siddiqui, Saad; Schwartz, Peter J; Shivkumar, Kalyanam; Ackerman, Michael JObjectives
This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).Background
LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.Methods
A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.Results
A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).Conclusions
In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.Item Open Access Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors.(Scientific reports, 2017-08-29) Hildebrandt, Michelle AT; Reyes, Monica; Wu, Xifeng; Pu, Xia; Thompson, Kara A; Ma, Jianzhong; Landstrom, Andrew P; Morrison, Alanna C; Ater, Joann LAnthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18-0.76, P = 0.0068) and 74% (95% CI: 0.07-0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.Item Open Access ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.(Journal of the American Heart Association, 2021-09) Moya-Mendez, Mary E; Ogbonna, Chiagoziem; Ezekian, Jordan E; Rosamilia, Michael B; Prange, Lyndsey; de la Uz, Caridad; Kim, Jeffrey J; Howard, Taylor; Garcia, John; Nussbaum, Robert; Truty, Rebecca; Callis, Thomas E; Funk, Emily; Heyes, Matthew; Dear, Guy de Lisle; Carboni, Michael P; Idriss, Salim F; Mikati, Mohamad A; Landstrom, Andrew PBackground Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of ATP1A3 genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), ATP1A3 variant status (positive versus negative), and ATP1A3 variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive ATP1A3 variant status (P<0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (P<0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. ATP1A3 genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in ATP1A3 were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. ATP1A3 variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.Item Open Access Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.(Molecular Genetics & Genomic Medicine, 2019-06) Headrick, Andrew T; Rosenfeld, Jill A; Yang, Yaping; Tunuguntla, Hari; Allen, Hugh D; Penny, Daniel J; Kim, Jeffrey J; Landstrom, Andrew PBACKGROUND:With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. METHODS:WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). RESULTS:Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals. CONCLUSIONS:Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic.