Genomes and Genes
Michael J Ackerman
Affiliation: Mayo Clinic
- Ostby S, Bos J, Owen H, Wackel P, Cannon B, Ackerman M. Competitive Sports Participation in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: A Single Center's Early Experience. JACC Clin Electrophysiol. 2016;2:253-262 pubmed publisher..Although sports participation is a risk taking behavior in undiagnosed and untreated CPVT, the risk may be acceptable for a well-treated and well-informed athlete following the diagnosis of CPVT. ..
- Giudicessi J, Ackerman M. Role of genetic heart disease in sentinel sudden cardiac arrest survivors across the age spectrum. Int J Cardiol. 2018;270:214-220 pubmed publisher..Although rare, GHDs can underlie SCA into adulthood and merit consideration across the age spectrum. ..
- Boczek N, Miller E, Ye D, Nesterenko V, Tester D, Antzelevitch C, et al. Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm. 2015;12:211-9 pubmed publisher..Therefore, expanded genetic testing in cases of TS to the entire CACNA1C coding region, if initial targeted testing is negative, may be warranted. ..
- Gaba P, Bos J, Cannon B, Cha Y, Friedman P, Asirvatham S, et al. Implantable cardioverter-defibrillator explantation for overdiagnosed or overtreated congenital long QT syndrome. Heart Rhythm. 2016;13:879-85 pubmed publisher..5 Â± 3.5 years of follow-up. Implications of overdiagnosis and overtreatment are profound because unnecessary ICD placement can be associated with infection, malfunction, inappropriate shocks, and subsequent anxiety. ..
- Pundi K, Bos J, Cannon B, Ackerman M. Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome. Heart Rhythm. 2015;12:776-81 pubmed publisher..Nevertheless, despite only 3 AED rescues in more than 1700 patient-years, an AED can be a lifesaving and cost-effective part of an LQTS patient's comprehensive sudden death prevention program. ..
- Ackerman M, Wylam M, Feldt R, Porter C, Dewald G, Scanlon P, et al. Pulmonary atresia with ventricular septal defect and persistent airway hyperresponsiveness. J Thorac Cardiovasc Surg. 2001;122:169-77 pubmed..Moreover, this at-risk patient population may yield unique insights into fundamental mechanisms involved in the pathogenesis of airway hyperresponsiveness. ..
- Ackerman M. Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue. Heart Rhythm. 2015;12:2325-31 pubmed publisher..Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant. ..
- Poterucha J, Bos J, Cannon B, Ackerman M. Frequency and severity of hypoglycemia in children with beta-blocker-treated long QT syndrome. Heart Rhythm. 2015;12:1815-9 pubmed publisher..A potential LQT2-hypoglycemia genotype-phenotype relationship warrants further investigation. ..
- Rohatgi R, Bos J, Ackerman M. Stimulant therapy in children with attention-deficit/hyperactivity disorder and concomitant long QT syndrome: A safe combination?. Heart Rhythm. 2015;12:1807-12 pubmed publisher..Physicians should find reassurance in the low adverse event rate and should weigh the potential effects of suboptimal treatment of ADHD with the theoretical proarrhythmic risk from stimulant medications. ..
- Tester D, Wong L, Chanana P, Jaye A, Evans J, Fitzpatrick D, et al. Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. J Am Coll Cardiol. 2018;71:1217-1227 pubmed publisher..These findings have major implications for the investigation of SIDS cases and families. ..
- Kapplinger J, Giudicessi J, Ye D, Tester D, Callis T, Valdivia C, et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015;8:582-95 pubmed publisher..Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant's pathogenic status. ..
- Anderson H, Bos J, Haugaa K, Morlan B, Tarrell R, Caraballo P, et al. Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System. Pediatr Cardiol. 2015;36:1350-6 pubmed publisher..However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS. ..
- Antiel R, Bos J, Joyce D, Owen H, Roskos P, Moir C, et al. Quality of life after videoscopic left cardiac sympathetic denervation in patients with potentially life-threatening cardiac channelopathies/cardiomyopathies. Heart Rhythm. 2016;13:62-9 pubmed publisher..Despite the anticipated side effects associated with LCSD, patients are satisfied with their surgery and indicate that they would recommend the surgery to another patient. ..
- Ackerman J, Bartos D, Kapplinger J, Tester D, Delisle B, Ackerman M. The Promise and Peril of Precision Medicine: Phenotyping Still Matters Most. Mayo Clin Proc. 2016;: pubmed publisher..As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing. ..
- Cortez D, Bos J, Ackerman M. Vectorcardiography identifies patients with electrocardiographically concealed long QT syndrome. Heart Rhythm. 2017;14:894-899 pubmed publisher..ecLQT3 was best differentiated by the fourth TwEV. VCG may facilitate familial diagnostic anticipation of LQTS status before the completion of mutation-specific genetic testing even with normal resting QTc values. ..
- Ackerman J, Smestad J, Tester D, Qureshi M, Crabb B, Mendelsohn N, et al. Whole Exome Sequencing, Familial Genomic Triangulation, and Systems Biology Converge to Identify a Novel Nonsense Mutation in TAB2-encoded TGF-beta Activated Kinase 1 in a Child with Polyvalvular Syndrome. Congenit Heart Dis. 2016;11:452-461 pubmed publisher..The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome. ..
- Kapplinger J, Pundi K, Larson N, Callis T, Tester D, Bikker H, et al. Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation. Circ Genom Precis Med. 2018;11:e001424 pubmed publisher..2% background rate that confounds RYR2 variant interpretation. ..
- Anderson J, Tester D, Will M, Ackerman M. Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young. Circ Cardiovasc Genet. 2016;9:259-65 pubmed publisher..Only 5 of the 100 interrogated sudden death genes hosted actionable pathogenic mutations for more than one third of these exertion-related, autopsy-negative SUDY cases. ..
- Weyhrauch D, Ye D, Boczek N, Tester D, Gavrilova R, Patterson M, et al. Whole Exome Sequencing and Heterologous Cellular Electrophysiology Studies Elucidate a Novel Loss-of-Function Mutation in the CACNA1A-Encoded Neuronal P/Q-Type Calcium Channel in a Child With Congenital Hypotonia and Developmental Delay. Pediatr Neurol. 2016;55:46-51 pubmed publisher..Genetic testing of CACNA1A in patients with congenital hypotonia and developmental delay may be warranted. ..
- Anderson H, Bos J, Kapplinger J, Meskill J, Ye D, Ackerman M. Lidocaine attenuation testing: An in vivo investigation of putative LQT3-associated variants in the SCN5A-encoded sodium channel. Heart Rhythm. 2017;14:1173-1179 pubmed publisher..Given that lidocaine acts as a late sodium current blocker, a positive LAT may enable the early identification of a pathological accentuation of the late sodium current that could be targeted therapeutically. ..
- Syed F, Ackerman M, McLeod C, Kapa S, Mulpuru S, Sriram C, et al. Sites of Successful Ventricular Fibrillation Ablation in Bileaflet Mitral Valve Prolapse Syndrome. Circ Arrhythm Electrophysiol. 2016;9: pubmed publisher..Ablation of clinically dominant VE foci improves symptoms and reduces appropriate implantable cardioverter defibrillator shocks. ..
- Altmann H, Tester D, Will M, Middha S, Evans J, Eckloff B, et al. Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome. Circulation. 2015;131:2051-60 pubmed publisher..All TRDN-null patients had strikingly similar phenotypes. Given the recurrent nature of potential lethal arrhythmias, patients fitting this phenotypic profile should undergo cardiac TRDN genetic testing. ..
- Ackerman M, VanDriest S, Ommen S, Will M, Nishimura R, Tajik A, et al. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective. J Am Coll Cardiol. 2002;39:2042-8 pubmed..Only 1% of unrelated individuals seen at a tertiary referral center for HCM possessed one of the five "malignant" mutations that were examined. Routine clinical testing for these specific mutations is of low yield. ..
- Ackerman M, Splawski I, Makielski J, Tester D, Will M, Timothy K, et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm. 2004;1:600-7 pubmed
- Boczek N, Ye D, Johnson E, Wang W, Crotti L, Tester D, et al. Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome. Circ Res. 2014;115:460-9 pubmed publisher..This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits Kv4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a Kv4.3 gain-of-function mechanism. ..
- Landstrom A, Boczek N, Ye D, Miyake C, DE LA Uz C, Allen H, et al. Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current. Int J Cardiol. 2016;220:290-8 pubmed publisher..TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations. ..
- Boczek N, Ye D, Jin F, Tester D, Huseby A, Bos J, et al. Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death. Circ Arrhythm Electrophysiol. 2015;8:1122-32 pubmed publisher..Arg518Cys/His is the pathogenic substrate for the observed phenotype. ..
- Clemens D, Lentino A, Kapplinger J, Ye D, Zhou W, Tester D, et al. Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign. Heart Rhythm. 2018;15:555-561 pubmed publisher..Of these, 29 were demoted because of their frequent sighting in gnomAD. Additionally, in silico analysis and in vitro functional studies have facilitated the demotion of 3 ultra-rare MVs (F127L, P477L, L619M). ..
- Sugrue A, Rohatgi R, Noseworthy P, Kremen V, Bos J, Qiang B, et al. Architectural T-Wave Analysis and Identification of On-Therapy Breakthrough Arrhythmic Risk in Type 1 and Type 2 Long-QT Syndrome. Circ Arrhythm Electrophysiol. 2017;10: pubmed publisher..Our aim was to evaluate the performance of a morphological T-wave analysis program in defining breakthrough LQTS arrhythmic risk beyond the QTc value...
- Rohatgi R, Sugrue A, Bos J, Cannon B, Asirvatham S, Moir C, et al. Contemporary Outcomes in Patients With Long QT Syndrome. J Am Coll Cardiol. 2017;70:453-462 pubmed publisher..Although outcomes have improved markedly, further optimization of treatment strategies is still needed given that 1 in 4 previously symptomatic patients experienced at least 1 subsequent, albeit nonlethal, LQTS-triggered cardiac event. ..
- Shanks G, Tester D, Nishtala S, Evans J, Ackerman M. Genomic Triangulation and Coverage Analysis in Whole-Exome Sequencing-Based Molecular Autopsies. Circ Cardiovasc Genet. 2017;10: pubmed publisher..In addition, autopsy-sourced DNA demonstrated strikingly lower whole-exome sequencing coverage than DNA from fresh blood draw. ..
- Ackerman M, Tester D, Jones G, Will M, Burrow C, Curran M. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc. 2003;78:1479-87 pubmed..This compendium provides a resource for epidemiological and functional investigation of variant effects on the repolarization properties of cardiac tissues, including susceptibility to lethal cardiac arrhythmias. ..
- Ackerman M, Siu B, Sturner W, Tester D, Valdivia C, Makielski J, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001;286:2264-9 pubmed