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Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing

Journal of Human Genetics (2024)Cite this article

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Abstract

Cardiac channelopathies are a group of heritable disorders that affect the heart’s electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

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Data availability

The datasets supporting the secondary findings of this article are included within the article and in the Supplementary Material. The datasets generated and analyzed during the current study have been made available for download at https://clingen.igib.res.in/cardioWGS/.

References

  1. Rahm A-K, Lugenbiel P, Schweizer PA, Katus HA, Thomas D. Role of ion channels in heart failure and channelopathies. Biophys Rev. 2018;10:1097–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Behere SP, Weindling SN. Inherited arrhythmias: the cardiac channelopathies. Ann Pediatr Cardiol. 2015;8:210–20.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fernández-Falgueras A, Sarquella-Brugada G, Brugada J, Brugada R, Campuzano O. Cardiac channelopathies and sudden death: recent clinical and genetic advances. Biology [Internet]. 2017 Jan 29;6. Available from: https://doi.org/10.3390/biology6010007

  4. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72:1046–59.

    Article  PubMed  Google Scholar 

  6. Funada A, Hayashi K, Ino H, Fujino N, Uchiyama K, Sakata K, et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol. 2008;31:270–4.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Leenhardt A, Denjoy I, Guicheney P. Catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2012;5:1044–52.

    Article  PubMed  Google Scholar 

  8. Bajaj A, Senthivel V, Bhoyar R, Jain A, Imran M, Rophina M, et al. 1029 genomes of self-declared healthy individuals from India reveal prevalent and clinically relevant cardiac ion channelopathy variants. Hum Genom. 2022;16:30.

    Article  CAS  Google Scholar 

  9. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795–803.

    Article  CAS  PubMed  Google Scholar 

  10. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805–11.

    Article  CAS  PubMed  Google Scholar 

  11. Campuzano O, Beltrán-Álvarez P, Iglesias A, Scornik F, Pérez G, Brugada R. Genetics and cardiac channelopathies. Genet Med. 2010;12:260–7.

  12. Musunuru K, Hershberger RE, Day SM, Klinedinst NJ, Landstrom AP, Parikh VN, et al. Genetic testing for inherited cardiovascular diseases: a scientific statement from the American Heart Association. Circ Genom Precis Med. 2020;13:e000067.

    Article  PubMed  Google Scholar 

  13. Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022;43:3997–4126.

    Article  PubMed  Google Scholar 

  14. Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Heart Rhythm. 2022;19:e1–60.

    Article  PubMed  Google Scholar 

  15. Adler A, Novelli V, Amin AS, Abiusi E, Care M, Nannenberg EA, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation 2020;141:418–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hosseini SM, Kim R, Udupa S, Costain G, Jobling R, Liston E, et al. Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome. Circulation 2018;138:1195–205.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Walsh R, Adler A, Amin AS, Abiusi E, Care M, Bikker H, et al. Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. Eur Heart J 2022;43:1500–10.

    Article  CAS  PubMed  Google Scholar 

  18. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AAM. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol. 2013;62:169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010;7:33–46.

    Article  PubMed  Google Scholar 

  20. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2:1099–105.

    Article  PubMed  Google Scholar 

  21. Leung KSK, Huang H, Chung CT, Radford D, Lakhani I, Li CKH, et al. Historical perspective and recent progress in cardiac ion channelopathies research and clinical practice in Hong Kong. J Inter Card Electrophysiol. 2023;24:1–10.

    Google Scholar 

  22. Ge HY, Li XM, Jiang H, Li MT, Zhang Y, Liu HJ. [Clinical characteristics and treatment of congenital long QT syndrome in 58 children]. Zhonghua Er Ke Za Zhi. 2019;57:272–6.

    CAS  PubMed  Google Scholar 

  23. Jiang H, Li X-M, Ge H-Y, Zhang Y, Liu H-J, Li M-T. Investigation of catecholaminergic polymorphic ventricular tachycardia children in China: clinical characteristics, delay to diagnosis, and misdiagnosis. Chin Med J. 2018;131:2864–5.

    PubMed  PubMed Central  Google Scholar 

  24. Vyas B, Puri RD, Namboodiri N, Saxena R, Nair M, Balakrishnan P, et al. Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes. Indian Pacing Electrophysiol J 2016;16:8–18.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dellefave-Castillo LM, Cirino AL, Callis TE, Esplin ED, Garcia J, Hatchell KE, et al. Assessment of the diagnostic yield of combined cardiomyopathy and arrhythmia genetic testing. JAMA Cardiol. 2022;7:966–74.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ewans LJ, Minoche AE, Schofield D, Shrestha R, Puttick C, Zhu Y, et al. Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis. Eur J Hum Genet. 2022;30:1121–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Di Resta C, Berg J, Villatore A, Maia M, Pili G, Fioravanti F, et al. Concealed substrates in Brugada syndrome: isolated channelopathy or associated cardiomyopathy? Genes [Internet]. 2022 Sep 28;13. Available from: https://doi.org/10.3390/genes13101755.

  28. Barc J, Tadros R, Glinge C, Chiang DY, Jouni M, Simonet F, et al. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. Nat Genet. 2022;54:232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. GUaRDIAN Consortium, Sivasubbu S, Scaria V. Genomics of rare genetic diseases-experiences from India. Hum Genom. 2019;14:52.

    Google Scholar 

  30. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 2014;30:2114–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv:1303.3997v2 [Preprint]. 2013 [cited 2013 May 26]: [3 p.]. Available from: http://arxiv.org/abs/1303.3997

  33. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence alignment/map format and SAMtools. Bioinformatics 2009;25:2078–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a mapreduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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.

    Article  PubMed  PubMed Central  Google Scholar 

  37. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GRS, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016;17:122.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581:434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32:1220–2.

    Article  CAS  PubMed  Google Scholar 

  40. Geoffroy V, Herenger Y, Kress A, Stoetzel C, Piton A, Dollfus H, et al. AnnotSV: an integrated tool for structural variations annotation. Bioinformatics. 2018;34:3572–4.

    Article  CAS  PubMed  Google Scholar 

  41. Lappalainen I, Lopez J, Skipper L, Hefferon T, Spalding JD, Garner J, et al. DbVar and DGVa: public archives for genomic structural variation. Nucleic Acids Res 2013;41:D936–41.

    Article  CAS  PubMed  Google Scholar 

  42. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen W-M. Robust relationship inference in genome-wide association studies. Bioinformatics 2010;26:2867–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Boczek NJ, Best JM, Tester DJ, Giudicessi JR, Middha S, Evans JM, et al. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet. 2013;6:279–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fukuyama M, Ohno S, Ozawa J, Kato K, Makiyama T, Nakagawa Y, et al. High prevalence of late-appearing T-wave in patients with long QT syndrome type 8. Circ J. 2020;84:559–68.

    Article  PubMed  Google Scholar 

  45. Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Huynh M-T, Proust A, Bouligand J, Popescu E. AKAP9-related channelopathy: novel pathogenic variant and review of the literature. Genes [Internet]. 2022 Nov 20;13. Available from: https://doi.org/10.3390/genes13112167.

  47. Jain A, Bhoyar RC, Pandhare K, Mishra A, Sharma D, Imran M, et al. IndiGenomes: a comprehensive resource of genetic variants from over 1000 Indian genomes. Nucleic Acids Res. 2021;49:D1225–32.

    CAS  PubMed  Google Scholar 

  48. Divakar MK, Jain A, Bhoyar RC, Senthivel V, Jolly B, Imran M, et al. Whole-genome sequencing of 1029 Indian individuals reveals unique and rare structural variants. J Hum Genet. 2023;68:409–17.

    Article  CAS  PubMed  Google Scholar 

  49. Shen C, Kong B, Liu Y, Xiong L, Shuai W, Wang G, et al. YY1-induced upregulation of lncRNA KCNQ1OT1 regulates angiotensin II-induced atrial fibrillation by modulating miR-384b/CACNA1C axis. Biochem Biophys Res Commun. 2018;505:134–40.

    Article  CAS  PubMed  Google Scholar 

  50. Ng K, Titus EW, Lieve KV, Roston TM, Mazzanti A, Deiter FH, et al. An international multicenter evaluation of inheritance patterns, arrhythmic risks, and underlying mechanisms of -catecholaminergic polymorphic ventricular tachycardia. Circulation. 2020;142:932–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dogan H, Can H, Otu HH. Whole genome sequence of a Turkish individual. PLoS One. 2014;9:e85233.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Jakobsson M, Scholz SW, Scheet P, Gibbs JR, VanLiere JM, Fung H-C, et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 2008;451:998–1003.

    Article  CAS  PubMed  Google Scholar 

  53. Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K, et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res. 2009;19:1682–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wong L-P, Ong RT-H, Poh W-T, Liu X, Chen P, Li R, et al. Deep whole-genome sequencing of 100 Southeast Asian Malays. Am J Hum Genet. 2013;92:52–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge late Prof. Rajnish Juneja for his pragmatic leadership in the implementation of genomics in clinical practice. The authors acknowledge the patients and their family members for their participation and cooperation throughout the study. The authors acknowledge Kavita Pandhare, Arushi Batra, Gyan Ranjan, and Vishu Gupta for their valuable input during the preparation of the manuscript.

Funding

This study was supported by funding from the Council of Scientific and Industrial Research, India (CSIR) and the Indian Council of Medical Research (ICMR) through grants OLP2301 and GAP0253, respectively. Authors AB, AVR, BJ, and MKD acknowledge the research fellowships from CSIR; Mohamed Imran acknowledges the research fellowship from ICMR. The funding bodies had no role in the analysis of data, preparation of the manuscript or decision to publish.

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Authors and Affiliations

  1. CSIR- Institute of Genomics and Integrative Biology, Mathura Road, Sukhdev Vihar, New Delhi, 110025, India

    Vigneshwar Senthivel, Bani Jolly, Arvinden VR, Anjali Bajaj, Rahul Bhoyar, Mohamed Imran, Harie Vignesh, Mohit Kumar Divakar, Vinod Scaria & Sridhar Sivasubbu

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Vigneshwar Senthivel, Bani Jolly, Arvinden VR, Anjali Bajaj, Mohamed Imran, Mohit Kumar Divakar, Vinod Scaria & Sridhar Sivasubbu

  3. Department of Cardiology, All India Institute of Medical Sciences, New Delhi, 110029, India

    Gautam Sharma, Nitin Rai, Kapil Kumar & Nitish Naik

  4. Government Medical College, Kozhikode, Kerala, 673008, India

    Jayakrishnan MP

  5. Tiny Hearts Fetal and Pediatric Clinic, Thanjavur, Tamil Nadu, 613001, India

    Maniram Krishna

  6. Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, 560069, India

    Jeyaprakash Shenthar & Muzaffar Ali

  7. Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India

    Shaad Abqari & Gulnaz Nadri

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  1. Vigneshwar Senthivel
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Contributions

Sridhar Sivasubbu, Vinod Scaria, Nitish Naik, and Vigneshwar Senthivel conceived the idea; Vigneshwar Senthivel, Bani Jolly, Arvinden VR, Mohamed Imran, Mohit Kumar Divakar, Harie Vignesh, Rahul Bhoyar and Anjali Bajaj performed research; Gautam Sharma, Nitin Rai, Kapil Kumar, Maniram Krishna, Jeyakrishnan MP, Jeyaprakash Shenthar, Muzaffar Ali, Shaad Abqari, Gulnaz Nadri carried out validation; Vigneshwar Senthivel, Rahul Bhoyar, Bani Jolly, Sridhar Sivasubbu wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All the authors have read and approved the final manuscript.

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Correspondence to Nitish Naik or Sridhar Sivasubbu.

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This study was approved by the Institutional Ethics Committee at the respective hospitals, AIIMS- New Delhi (Ethics No: IEC-855/06.12.2019, RP-47/2020) and CSIR- Institute of Genomics and Integrative Biology, New Delhi, India (Ethics No: CSIR-IGIB/IHEC/2020-21/02). Additionally, written informed consent to participate in this study was provided by the participants or their legal guardian.

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Senthivel, V., Jolly, B., VR, A. et al. Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01265-2

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