An initiative to uncover Indian population-specific gene variations of cardiac channelopathies by CSIR-IGIB

on

Aswini B | 08 February 2020

 The heart is the first organ formed during vertebrate development. The musculature of the heart provides it with an amazing property of involuntary and sequential excitation and contraction of the heart. This is called cardiac rhythm. It is produced as a response to the electrical impulse generated by the sino-atrial node (SAN) also called the pacemaker of the heart, which gets transmitted to the different components of the electrical conduction system of the heart. This sequential movement of electrical impulses from one part of the heart to another produces an electrical current, leading to the sequential cardiac rhythm.

 The electrical stability of the heart is very crucial in maintaining its normal rhythm. Instability in the electrical network caused by genetic abnormalities in the ion channels leads to disturbances in the heart rhythm and are called cardiac channelopathies or cardiac arrhythmias. It is the prime cause of sudden cardiac death in young individuals.

 Symptoms of cardiac channelopathies include confusion, trouble concentrating, tiredness, dizziness, fainting etc. Current treatment is medications for beta-blockers. In severe cases, a small battery-operated device which can detect and stop abnormal heartbeats is implanted. It is called the implantable cardioverter-defibrillator (ICD) (1).

The Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA) and Asia Pacific Heart Rhythm Society (APHRS) classify inherited primary arrhythmia syndromes or channelopathies into 8 types. These primarily include Long QT Syndrome, Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia and Short QT Syndrome among others (2). More than 35 genes are reported to be associated with these conditions. They can advance into life-threatening arrhythmias eventually leading to sudden cardiac death. Genotypic and phenotypic heterogeneity is a hallmark of these conditions (3).
Art by Vigneshwar Senthivel who works on Cardiac Channelopathies in
CSIR-IGIB
Congenital Long QT Syndrome (LQTS) is the most prevalent and studied cardiac channelopathies. The incidence of congenital LQTS is 1 in 5000 (4). About 17 genes are associated with Long QT Syndrome. The 3 crucial genes - KCNQ1, KCNH2 and SCN5A attribute to 75% of the cases. The remaining 14 genes account for less than 5% of the phenotype and are thus called the minor genes. The cause for the rest 20% of the cases remains unknown (5). LQTS is associated with the risk of sudden cardiac death in young patients and poses a massive socio-economic burden.

 Brugada Syndrome is inherited in an autosomal dominant manner. Its global prevalence is around 0.5 in 1000. However, its prevalence varies in different parts of the world. The highest prevalence is in south-east Asia with 3.7 in 1000 (6). It represents around 4% - 12% of all sudden cardiac deaths (7). About 18 genes are associated with Brugada Syndrome but the crucial gene is SCN5A. It attributes to approximately 15% - 30% of the cases. Yet the genetic cause of 65% - 70% of the clinically diagnosed cases remain unknown (8).

 Short QT syndrome is rare. It is inherited in an autosomal dominant pattern. However, it can occur sporadically as well. Key genes involved in short QT syndrome are KCNH2, KCNJ2 and KCNQ1 (9). Though the prevalence of short QT syndrome is not known, around 200 cases have been reported in the literature. However, it may be underdiagnosed since some patients may never experience symptoms. Mutations have been identified in 8 ion channel subunits and 7 of them have demonstrated causality (10).

 The exact prevalence of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is unknown. However, it is estimated to be around 1 in 10,000. RYR2 and CASQ2 are the genes associated with CPVT. Mutations in the RYR2 gene causes around half the CPVT cases and 1% - 2% of the cases have CASQ2 gene mutations. The genetic cause of the remaining patients remains unknown. Mutations in the RYR2 gene are inherited in an autosomal dominant manner while mutations in the CASQ2 gene are inherited in an autosomal recessive manner (11).

 The understanding of genotype-phenotype correlation has improved over the last few decades. Genetic screening plays a significant role in determining the risk of developing certain diseases. A genetic screening result, along with the patient's symptoms helps to diagnose the disease condition. However, a positive result does not guarantee the development of a disease. Genetic diagnosis aids in determining the exact mutation associated with a particular gene. Once a particular gene mutation is ascertained, it helps the medical practitioner to decide on timely intervention and gene-targeted treatments. It also assists in determining the beneficial and effective medicine and dosage for the patient. Since genetic conditions run in families, a positive report urges the family members to determine their carrier status to learn about their susceptibility to the particular disease condition.

Many cohort-based studies have revealed the population-specific mutation spectrum of the Long QT Syndrome. They have also identified novel gene variations. This signifies the importance of population genetics, which could reveal mutations specific to a particular ethnic group. However, India, which is home to multiple ethnic groups, holds only 2 studies which report mutations associated with the disease (12,13). The literature-based survey indicates that the mutation landscape of India is very different from the world (14,15) and there is a clear gap in knowledge about the mutation spectrum specific to the Indian population. This emphasizes the need to explore the mutation spectrum in the context of the Indian population.

 The GuARDIAN consortium in CSIR-Institute of Genomics and Integrated Biology has put together a patient cohort of cardiac channelopathies from a tertiary medical centre. The consortium aims to find out the Indian population-specific gene variations associated with cardiac channelopathies through exome analysis.

Though few common gene variations have been observed in the patients, a large number of cases remain unsolved due to a huge burden of variations of uncertain significance (VUS). These VUS needs functional validation to classify them as benign or pathogenic. Once the classification is achieved, we will have baseline gene variation information for the risk of cardiac channelopathies in Indian population. This data is crucial to enable fast and precise diagnosis allowing appropriate therapeutic decisions.

 To create awareness and to bridge the gap between researchers and clinicians various meetings have been conducted regarding the ongoing research about cardiovascular genomics. These meetings covered various areas of cardiovascular biology including the genetics of fetal cardiac anomalies, congenital heart disease, sudden cardiac death, Arrhythmia syndromes like long QT, Brugada syndrome, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, pharmacogenomics and genetic counselling in cardiovascular diseases.

 To find out more about the ongoing research about cardiac channelopathies, log on to http://guardian.meragenome.com/cardiac-arrhythmia

 References

1. Fu DG. Cardiac arrhythmias: Diagnosis, symptoms, and treatments. Cell biochemistry and biophysics. 2015 Nov 1;73(2):291-6.
2. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart rhythm. 2013 Dec 1;10(12):1932-63.
3. Campuzano O, Sarquella-Brugada G, Brugada R, Brugada J. Genetics of channelopathies associated with sudden cardiac death. Global Cardiology Science and Practice. 2015 Oct 6;2015(3):39.
4. Kaur M, Ramakumar N, Yadav S, Subramaniam R. Recurrent syncope in a child and video-assisted thoracoscopic surgery - The long and short of it. Indian J Anaesth 2019;63:847-50
5. Giudicessi JR, Wilde AA, Ackerman MJ. The genetic architecture of long QT syndrome: a critical reappraisal. Trends in cardiovascular medicine. 2018 Oct 1;28(7):453-64.
6. Vutthikraivit, Wasawat et al. “Worldwide Prevalence of Brugada Syndrome: A Systematic Review and Meta-Analysis.” Acta Cardiologica Sinica vol. 34,3 (2018): 267-277. DOI:10.6515/ACS.201805_34(3).20180302B
7. Giuseppe, C., Egle, C., Antonio, C., Giampiero, M., Domenico, O., Antonino, M., & Brugada, P. (2019). Update on Brugada Syndrome 2019. Current Problems in Cardiology, 100454. DOI:10.1016/j.cpcardiol.2019.100454
8. https://rarediseases.org/rare-diseases/brugada-syndrome/
9. https://ghr.nlm.nih.gov/condition/short-qt-syndrome#
10. Hancox, J.C., Whittaker, D.G., Zhang, H. et al. Learning from studying very rare cardiac conditions: the example of short QT syndrome. J Congenit Heart Dis 3, 3 (2019).
11. https://ghr.nlm.nih.gov/condition/catecholaminergic-polymorphic-ventricular-tachycardia#statistics
12. Qureshi SF, Ali A, Venkateshwari A, Rao H, Jayakrishnan MP, Narasimhan C, Shenthar J, Thangaraj K, Nallari P. Genotype-phenotype correlation in long QT syndrome families. Indian pacing and electrophysiology journal. 2015 Nov 1;15(6):269-85.
13. Vyas B, Puri RD, Namboodiri N, Saxena R, Nair M, Balakrishnan P, Jayakrishnan MP, Udyavar A, Kishore R, Verma IC. Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes. Indian pacing and electrophysiology journal. 2016 Jan 1;16(1):8-18.
14. Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep 1;6(9):1297-303.
15. Edelmann J, Dobosz T, Sobieszczanska M, Kawecka-Negrusz M, Dreßler J, Nastainczyk-Wulf M. Mutation analysis for the detection of long QT-syndrome (LQTS) associated SNPs. International journal of legal medicine. 2017 Mar 1;131(2):333-8.