Electrocardiographic Assessment and Genetic Analysis in Neonates: a Current Topic of Discussion

Author(s): Georgia Sarquella-Brugada, Sergi Cesar, Maria Dolores Zambrano, Anna Fernandez-Falgueras, Victoria Fiol, Anna Iglesias, Francesc Torres, Oscar Garcia-Algar, Elena Arbelo, Josep Brugada, Ramon Brugada, Oscar Campuzano*

Journal Name: Current Cardiology Reviews

Volume 15 , Issue 1 , 2019

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Graphical Abstract:


Background: Sudden death of a newborn is a rare entity, which may be caused by genetic cardiac arrhythmias. Among these diseases, Long QT syndrome is the most prevalent arrhythmia in neonates, but other diseases such as Brugada syndrome, Short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia also cause sudden death in infants. All these entities are characterized by well-known alterations in the electrocardiogram and the first symptom of the disease may be an unexpected death. Despite the low prevalence of these diseases, the performance of an electrocardiogram in the first hours or days after birth could help identify these electrical disruptions and adopt preventive measures. In recent years, there has been an important impulse by some experts in the scientific community towards the initiation of a newborn electrocardiogram-screening program, for the detection of these electrocardiographic abnormalities. In addition, the use of genetic analysis in neonates could identify the cause of these heart alterations. Identification of relatives carrying the genetic alteration associated with the disease allows adoption of measures to prevent lethal episodes.

Conclusion: Recent technological advances enable a comprehensive genetic screening of a large number of genes in a cost-effective way. However, the interpretation of genetic data and its translation into clinical practice are the main challenges for cardiologists and geneticists. However, there is important controversy as to the clinical value, and cost-effectiveness of the use of electrocardiogram as well as of genetic testing to detect these cases. Our review focuses on these current matters of argue.

Keywords: Electrocardiogram, neonates, arrhythmia, sudden cardiac death, long QT syndrome, genetics.

Priori SG, Blomstrom-Lundqvist C. 2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. Eur Heart J 2015; 36: 2757-9.
Rodriguez-Calvo MS, Brion M, Allegue C, Concheiro L, Carracedo A. Molecular genetics of sudden cardiac death. Forensic Sci Int 2008; 182: 1-12.
Behr ER, Dalageorgou C, Christiansen M, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008; 29: 1670-80.
Raju H, Behr ER. Unexplained sudden death, focussing on genetics and family phenotyping. Curr Opin Cardiol 2013; 28: 19-25.
Giudici V, Spanaki A, Hendry J, et al. Sudden arrhythmic death syndrome: Diagnostic yield of comprehensive clinical evaluation of pediatric first-degree relatives. Pacing Clin Electrophysiol 2014; 37(12): 1681-5.
Krous HF, Beckwith JB, Byard RW, et al. Sudden infant death syndrome and unclassified sudden infant deaths: A definitional and diagnostic approach. Pediatrics 2004; 114: 234-8.
Moon RY, Fu L. Sudden infant death syndrome: An update. Pediatr Rev 2012; 33: 314-20.
Baruteau AE, Tester DJ, Kapplinger JD, Ackerman MJ, Behr ER. Sudden infant death syndrome and inherited cardiac conditions. Nat Rev Cardiol 2017; 14: 715-26.
Filiano JJ, Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol Neonate 1994; 65: 194-7.
Goldwater PN. A perspective on SIDS pathogenesis. the hypotheses: Plausibility and evidence. BMC Med 2011; 9: 64.
Campuzano O, Allegue C, Partemi S, Iglesias A, Oliva A, Brugada R. Negative autopsy and sudden cardiac death. Int J Legal Med 2014; 128: 599-606.
Van Niekerk C, Van Deventer BS, du Toit-Prinsloo L. Long QT syndrome and sudden unexpected infant death. J Clin Pathol 2017; 70: 808-13.
Tester DJ, Wong LCH, Chanana P, et al. Cardiac genetic predisposition in sudden infant death syndrome. J Am Coll Cardiol 2018; 71: 1217-27.
Fernandez-Falgueras A, Sarquella-Brugada G, Brugada J, Brugada R, Campuzano O. Cardiac channelopathies and sudden death: Recent clinical and genetic advances. Biology 2017; 6(1): E7.
Schimpf R, Veltmann C, Wolpert C, Borggrefe M. Channelopathies: Brugada syndrome, long QT syndrome, short QT syndrome, and CPVT. Herz 2009; 34: 281-8.
Campuzano O, Sarquella-Brugada G, Brugada R, Brugada J. Genetics of channelopathies associated with sudden cardiac death. Glob Cardiol Sci Pract 2015; 2015: 39.
Wilders R. Cardiac ion channelopathies and the sudden infant death syndrome. ISRN Cardiol 2012; 2012: 846171.
Davis AM, Glengarry J, Skinner JR. Sudden infant death: QT or not QT? That is no longer the question. Circ Arrhythm Electrophysiol 2016; 9: e003859.
Crotti L, Celano G, Dagradi F, Schwartz PJ. Congenital long QT syndrome. Orphanet J Rare Dis 2008; 3: 18.
Schwartz PJ, Ackerman MJ. The long QT syndrome: A transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34: 3109-16.
Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: From genetics to management. Circ Arrhythm Electrophysiol 2012; 5: 868-77.
Campuzano O, Sarquella-Brugada G, Cesar S, et al. Genetics of inherited arrhythmias in pediatrics. Curr Opin Pediatr 2015; 27: 665-74.
Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007; 115: 361-7.
Stattin EL, Westin IM, Cederquist K, et al. Genetic screening in sudden cardiac death in the young can save future lives. Int J Legal Med 2016; 130: 59-66.
Glengarry JM, Crawford J, Morrow PL, Stables SR, Love DR, Skinner JR. Long QT molecular autopsy in sudden infant death syndrome. Arch Dis Child 2014; 99: 635-40.
Wilde AA, Moss AJ, Kaufman ES, et al. Clinical aspects of type 3 long-QT syndrome: An international multicenter study. Circulation 2016; 134: 872-82.
Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: A new clinical syndrome? Cardiology 2000; 94: 99-102.
Mazzanti A, Kanthan A, Monteforte N, et al. Novel insight into the natural history of short QT syndrome. J Am Coll Cardiol 2014; 63: 1300-8.
Pereira R, Campuzano O, Sarquella-Brugada G, et al. Short QT syndrome in pediatrics. Clin Res Cardiol 2017; 106(6): 393-400.
Behere SP, Weindling SN. Inherited arrhythmias: The cardiac channelopathies. Ann Pediatr Cardiol 2015; 8: 210-20.
Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 2004; 109: 30-5.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: A distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992; 20: 1391-6.
Gehi AK, Duong TD, Metz LD, Gomes JA, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: A meta-analysis. J Cardiovasc Electrophysiol 2006; 17: 577-83.
Benito B, Brugada R, Brugada J, Brugada P. Brugada syndrome. Prog Cardiovasc Dis 2008; 51: 1-22.
Brugada R, Campuzano O, Sarquella-Brugada G, Brugada J, Brugada P. Brugada syndrome. Methodist DeBakey Cardiovasc J 2014; 10: 25-8.
Sarquella-Brugada G, Campuzano O, Arbelo E, Brugada J, Brugada R. Brugada syndrome: Clinical and genetic findings. Genet Med 2016; 18: 3-12.
Priori SG, Napolitano C, Giordano U, Collisani G, Memmi M. Brugada syndrome and sudden cardiac death in children. Lancet 2000; 355: 808-9.
Refaat MM, Hassanieh S, Scheinman M. Catecholaminergic polymorphic ventricular tachycardia. Card Electrophysiol Clin 2016; 8: 233-7.
Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106: 69-74.
Ylanen K, Poutanen T, Hiippala A, Swan H, Korppi M. Catecholaminergic polymorphic ventricular tachycardia. Eur J Pediatr 2010; 169: 535-42.
Tester DJ, Dura M, Carturan E, et al. A mechanism for Sudden Infant Death Syndrome (SIDS): Stress-induced leak via ryanodine receptors. Heart Rhythm 2007; 4: 733-9.
Neubauer J, Lecca MR, Russo G, et al. Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet 2017; 25: 404-9.
Klaver EC, Versluijs GM, Wilders R. Cardiac ion channel mutations in the sudden infant death syndrome. Int J Cardiol 2011; 152: 162-70.
Dettmeyer RB, Kandolf R. Cardiomyopathies--misdiagnosed as Sudden Infant Death Syndrome (SIDS). Forensic Sci Int 2010; 194: e21-4.
Semsarian C, Bagnall RD. Sudden cardiac death in children and young adults. N Engl J Med 2016; 375: 1301-2.
Semsarian C, Ingles J. Molecular autopsy in victims of inherited arrhythmias. J Arrhythm 2016; 32: 359-65.
Michaud K, Mangin P, Elger BS. Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices. Int J Legal Med 2011; 125: 359-66.
Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace 2011; 13: 1077-109.
Hertz CL, Christiansen SL, Larsen MK, et al. Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Hum Genet 2016; 24: 817-22.
Brion M, Allegue C, Santori M, et al. Sarcomeric gene mutations in sudden infant death syndrome (SIDS). Forensic Sci Int 2012; 219: 278-81.
Campuzano O, Allegue C, Sarquella-Brugada G, et al. The role of clinical, genetic and segregation evaluation in sudden infant death. Forensic Sci Int 2014; 242: 9-15.
Sarquella-Brugada G, Campuzano O, Cesar S, et al. Sudden infant death syndrome caused by cardiac arrhythmias: Only a matter of genes encoding ion channels? Int J Legal Med 2016; 130: 415-20.
Faita F, Vecoli C, Foffa I, Andreassi MG. Next generation sequencing in cardiovascular diseases. World J Cardiol 2012; 4: 288-95.
Sanchez O, Campuzano O, Fernandez-Falgueras A, et al. Natural and undetermined sudden death: Value of post-mortem genetic investigation. PLoS One 2016; 11: e0167358.
Campuzano O, Sarquella-Brugada G, Mademont-Soler I, et al. Identification of genetic alterations, as causative genetic defects in long qt syndrome, using next generation sequencing technology. PLoS One 2014; 9: e114894.
Williams VS, Cresswell CJ, Ruspi G, et al. Multiplex ligation-dependent probe amplification copy number variant analysis in patients with acquired long QT syndrome. Europace 2015; 17: 635-41.
Priest JR, Ceresnak SR, Dewey FE, et al. Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing. Heart Rhythm 2014; 11: 1707-13.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-24.
Amendola LM, Jarvik GP, Leo MC, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium. Am J Hum Genet 2016; 98: 1067-76.
Campuzano O, Allegue C, Fernandez A, Iglesias A, Brugada R. Determining the pathogenicity of genetic variants associated with cardiac channelopathies. Sci Rep 2015; 5: 7953.
Ziegler RF. Characteristics of the unipolar precordial electrocardiogram in normal infants. Circulation 1951; 3: 438-43.
Rijnbeek PR, Witsenburg M, Schrama E, Hess J, Kors JA. New normal limits for the paediatric electrocardiogram. Eur Heart J 2001; 22: 702-11.
Brockmeier K, Nazal R, Sreeram N. The electrocardiogram of the neonate and infant. J Electrocardiol 2016; 49: 814-6.
Saul JP, Schwartz PJ, Ackerman MJ, Triedman JK. Rationale and objectives for ECG screening in infancy. Heart Rhythm 2014; 11: 2316-21.
Skinner JR, Van Hare GF. Routine ECG screening in infancy and early childhood should not be performed. Heart Rhythm 2014; 11: 2322-7.
Schwartz PJ, Priori SG, Bloise R, et al. Molecular diagnosis in a child with sudden infant death syndrome. Lancet 2001; 358: 1342-3.
Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338: 1709-14.
Schwartz PJ, Stramba-Badiale M, Crotti L, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009; 120: 1761-7.
Stramba-Badiale M, Karnad DR, Goulene KM, et al. For neonatal ECG screening there is no reason to relinquish old Bazett’s correction. Eur Heart J 2018; 39(31): 2888-95.
Kligfield P, Gettes LS, Bailey JJ, et al. Recommendations for the standardization and interpretation of the electrocardiogram: Part I: The electrocardiogram and its technology a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol 2007; 49: 1109-27.
Murphy MC, Angelis L, Fitzgerald E, McCarthy LK. ODonnell CPF. Randomised crossover study comparing speed of heart rate display in newborns using ECG plus pulse oximeter versus pulse oximeter alone. Arch Dis Child Fetal Neonatal Ed 2017; 102: F464-5.
Murphy MC, De Angelis L, McCollum D, McCarthy LK, O’Donnell CP. A randomised cross-over study of methods of acquiring ECG heart rate in newborns. Arch Dis Child Fetal Neonatal Ed 2017; 102: F369-70.
Gonzalez FM, Veneziano MA, Puggina A, Boccia S. A systematic review on the cost-effectiveness of genetic and electrocardiogram testing for long QT syndrome in infants and young adults. Value Health 2015; 18: 700-8.
McCorquodale A, Poulton R, Hendry J, et al. High prevalence of early repolarization in the paediatric relatives of sudden arrhythmic death syndrome victims and in normal controls. Europace 2017; 19: 1385-91.
Chan TC, Sharieff GQ, Brady WJ. Electrocardiographic manifestations: Pediatric ECG. J Emerg Med 2008; 35: 421-30.

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Article Details

Year: 2019
Published on: 11 December, 2018
Page: [30 - 37]
Pages: 8
DOI: 10.2174/1573403X14666180913114806
Price: $65

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