Genetic analysis of Iranian family with hereditary cardiac arrhythmias by next generation sequencing

Authors

1 Department of Genetic and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran

2 Cardiovascular Research Institute, and Genome Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

3 Department of Cardiovascular Disease, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Cardiac arrhythmias are responsible for several cases of syncope and sudden cardiac death annually worldwide. Due to overlapping clinical symptoms in some cardiac arrhythmias genetic studies would help to confirm the primary clinical diagnosis made on the basis of solely clinical findings. In addition clinical management of the patient, family screening and provide appropriate counseling and risk assessment for the family members are other advantages of genetic study.
Materials and Methods: Totally nine patients from a family included in this study. The primary diagnosis on the basis of clinical findings was second-degree atrioventricular (AV) block for this family. Mutation in SCN5A gene is frequently reported for second-degree AV block and hence the gene was analyzed using whole gene sequencing but no mutation was detected. Subsequently, the samples were subjected to customized Ampliseq 77 gene panel using next generation sequencing to detect the underlying molecular defects.




Results: We found c. 5570T>A missense mutation in ANK2 gene for this family. Based on the Online Mendelian Inheritance in Man, ANK2 gene and the mutation detected correspond to long QT syndrome type 4.




Conclusion: This mutation, although already known in other populations, but is reported for the first time in Iranian patients with cardiac arrhythmias. As the case with this family, genetic analysis of patients with cardiac arrhythmias would be helpful in reassessment of clinical diagnosis and therefore would help for patients' management and in some cases re-evaluation of ongoing treatment may be needed.

Keywords

1.
Berger S, Kugler JD, Thomas JA, Friedberg DZ. Sudden cardiac death in children and adolescents: Introduction and overview. Pediatr Clin North Am 2004;51:1201-9.  Back to cited text no. 1
    
2.
Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA. Sudden unexplained death: Heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005;112:207-13.  Back to cited text no. 2
    
3.
Bhuiyan ZA, Momenah TS, Amin AS, Al-Khadra AS, Alders M, Wilde AA, et al. An intronic mutation leading to incomplete skipping of exon-2 in KCNQ1 rescues hearing in Jervell and Lange-Nielsen syndrome. Prog Biophys Mol Biol 2008;98:319-27.  Back to cited text no. 3
    
4.
Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, et al. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: A comprehensive open reading frame mutational analysis. J Am Coll Cardiol 2009;54:2065-74.  Back to cited text no. 4
    
5.
Bhuiyan ZA, Wilde AA. Familial arrhythmias - Genes, mechanisms and treatment: Present perspective, heart disease in men. New York, USA: Nova Science Publisher; 2009; p. 3-44.  Back to cited text no. 5
    
6.
Bhuiyan ZA, Momenah TS, Gong Q, Amin AS, Ghamdi SA, Carvalho JS, et al. Recurrent intrauterine fetal loss due to near absence of HERG: Clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. Heart Rhythm 2008;5:553-61.  Back to cited text no. 6
    
7.
Bhuiyan ZA, van den Berg MP, van Tintelen JP, Bink-Boelkens MT, Wiesfeld AC, Alders M, et al. Expanding spectrum of human RYR2-related disease: New electrocardiographic, structural, and genetic features. Circulation 2007;116:1569-76.  Back to cited text no. 7
    
8.
Wilde AA, Bhuiyan ZA, Crotti L, Facchini M, De Ferrari GM, Paul T, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008;358:2024-9.  Back to cited text no. 8
    
9.
van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244-54.  Back to cited text no. 9
    
10.
Ware JS, John S, Roberts AM, Buchan R, Gong S, Peters NS, et al. Next generation diagnostics in inherited arrhythmia syndromes: A comparison of two approaches. J Cardiovasc Transl Res 2013;6:94-103.  Back to cited text no. 10
    
11.
Nawathe PA, Kryukova Y, Oren RV, Milanesi R, Clancy CE, Lu JT, et al. An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. J Cardiovasc Electrophysiol 2013;24:1021-7.  Back to cited text no. 11
    
12.
Millat G, Chanavat V, Rousson R. Evaluation of a new high-throughput next-generation sequencing method based on a custom AmpliSeq™ library and ion torrent PGM™ sequencing for the rapid detection of genetic variations in long QT syndrome. Mol Diagn Ther 2014;18:533-9.  Back to cited text no. 12
    
13.
Medeiros-Domingo A, Iturralde-Torres P, Ackerman MJ. Clinical and genetic characteristics of long QT syndrome. Rev Esp Cardiol 2007;60:739-52.  Back to cited text no. 13
    
14.
Sedlacek K, Stark K, Cunha SR, Pfeufer A, Weber S, Berger I, et al. Common genetic variants in ANK2 modulate QT interval: Results from the KORA study. Circ Cardiovasc Genet 2008;1:93-9.  Back to cited text no. 14
    
15.
Mohler PJ, Hoffman JA, Davis JQ, Abdi KM, Kim CR, Jones SK, et al. Isoform specificity among ankyrins. An amphipathic alpha-helix in the divergent regulatory domain of ankyrin-b interacts with the molecular co-chaperone Hdj1/Hsp40. J Biol Chem 2004;279:25798-804.  Back to cited text no. 15
    
16.
Zhou X, Shimizu M, Konno T, Ino H, Fujino N, Uchiyama K, et al. Analysis of ankyrin-B gene mutations in patients with long QT syndrome. Nan Fang Yi Ke Da Xue Xue Bao 2006;26:901-3, 909.  Back to cited text no. 16
    
17.
Mohler PJ, Gramolini AO, Bennett V. Ankyrins. J Cell Sci 2002;115:1565-6.  Back to cited text no. 17
    
18.
Liang P, Liu W, Li C, Tao W, Li L, Hu D. Genetic analysis of Brugada syndrome and congenital long-QT syndrome type 3 in the Chinese. J Cardiovasc Dis Res 2010;1:69-74.  Back to cited text no. 18
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