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Molecular analysis of dilated and left ventricular noncompaction cardiomyopathies in Egyptian children

Published online by Cambridge University Press:  26 May 2021

Dina A. Mehaney Open the ORCID record for Dina A. Mehaney [Opens in a new window] ,
Alireza Haghighi ,
Amira K. Embaby Open the ORCID record for Amira K. Embaby [Opens in a new window] ,
Reham A. Zeyada ,
Rania K. Darwish ,
Nesrine S. Elfeel ,
Mohamed Abouelhoda ,
Sonia A. El-Saiedi ,
Nadida A. Gohar  and
Zeinab S. Seliem
Dina A. Mehaney*
Affiliation:
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt Next Generation Sequencing Laboratory, Cairo University Children Hospital, Egypt
Alireza Haghighi
Affiliation:
Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, MA, USA
Amira K. Embaby
Affiliation:
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Reham A. Zeyada
Affiliation:
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Rania K. Darwish
Affiliation:
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt Next Generation Sequencing Laboratory, Cairo University Children Hospital, Egypt
Nesrine S. Elfeel
Affiliation:
Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Mohamed Abouelhoda
Affiliation:
Systems and Biomedical Engineering Department, Faculty of Engineering, Cairo University, Cairo, Egypt
Sonia A. El-Saiedi
Affiliation:
Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Nadida A. Gohar
Affiliation:
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
Zeinab S. Seliem
Affiliation:
Pediatrics Department, Faculty of Medicine, Cairo University, Cairo, Egypt
*
Author for correspondence: Dr D. A. Mehaney, MD, Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Kasr Alainy St., Cairo, 11562, Egypt. Tel: +201023123423; Fax: +2023644383. E-mail: [email protected]
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Abstract

Background:

Paediatric cardiomyopathy is a progressive, often lethal disorder and the most common cause of heart failure in children. Despite its severe outcomes, the genetic aetiology is still poorly characterised. High-throughput sequencing offers a great opportunity for a better understanding of the genetic causes of cardiomyopathy.

Aim:

The current study aimed to elucidate the genetic background of cardiomyopathy in Egyptian children.

Methods:

This hospital-based study involved 68 patients; 58 idiopathic primary dilated cardiomyopathy and 10 left ventricular noncompaction cardiomyopathy. Cardiomyopathy-associated genes were investigated using targeted next-generation sequencing.

Results:

Consanguinity was positive in 53 and 70% of dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy patients, respectively. Positive family history of cardiomyopathy was present in 28% of dilated cardiomyopathy and 10% of the left ventricular noncompaction cardiomyopathy patients. In 25 patients, 29 rare variants were detected; 2 likely pathogenic variants in TNNI3 and TTN and 27 variants of uncertain significance explaining 2.9% of patients.

Conclusions:

The low genetic detection rate suggests that novel genes or variants might underlie paediatric cardiomyopathy in Egypt, especially with the high burden of consanguinity. Being the first national and regional report, our study could be a reference for future genetic testing in Egyptian cardiomyopathy children. Genome-wide tests (whole exome/genome sequencing) might be more suitable than the targeted sequencing to investigate the primary cardiomyopathy patients. Molecular characterisation of cardiomyopathies in different ethnicities will allow for global comparative studies that could result in understanding the pathophysiology and heterogeneity of cardiomyopathies.

Keywords

Dilated cardiomyopathyleft ventricular noncompaction cardiomyopathynext-generation sequencingpaediatricsEgypt
Type
Original Article
Information
Cardiology in the Young , Volume 32 , Issue 2 , February 2022 , pp. 295 - 300
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Copyright
© The Author(s), 2021. Published by Cambridge University Press

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Footnotes

*

Dina A. Mehaney, Alireza Haghighi, Rania K. Darwish, and Mohamed Abouelhoda are first authors on this review with a shared first co-authorship.

**

Sonia A. El-Saiedi, Nadida A. Gohar, and Zeinab S. Seliem Elhoda are the last authors on this review with a shared last co-authorship.

References

Choudhry, S, Puri, K, Denfield, SW. An update on pediatric cardiomyopathy. Curr Treat Options Cardiovasc Med 2019; 21: 36.10.1007/s11936-019-0739-yCrossRefGoogle ScholarPubMed
Lipshultz, SE, Law, YM, Asante-Korang, A, et al. cardiomyopathy in children: classification and diagnosis: a scientific statement from the American Heart Association. Circulation 2019; 140: E9–E68.CrossRefGoogle ScholarPubMed
Merlo, M, Pivetta, A, Pinamonti, B, et al. Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years. Eur J Heart Fail 2014; 16: 317–324.10.1002/ejhf.16CrossRefGoogle ScholarPubMed
Elmasry, OA, Kamel, TB, El-Feki, NF. Pediatric cardiomyopathies over the last decade: a retrospective observational epidemiology study in a tertiary institute, Egypt. J Egypt Public Health Assoc 2011; 86: 63–67.10.1097/01.EPX.0000399140.68151.6aCrossRefGoogle Scholar
Bakeet, M, Montaser, MM, Allam, AA, Gamal, R. Childhood cardiomyopathies: a study in tertiary care hospital in Upper Egypt. Electron Physician 2016; 8: 3164–3169.CrossRefGoogle ScholarPubMed
Adadi, N, Radi, FZ, Lahrouchi, N, et al. Inherited dilated cardiomyopathy in a large moroccan family caused by LMNA mutation. Anatol J Cardiol 2018; 20: 65–68.Google Scholar
Yotti, R, Seidman, CE, Seidman, JG. Advances in the genetic basis and pathogenesis of sarcomere cardiomyopathies. Annu Rev Genomics Hum Genet 2019; 20: 129–153.10.1146/annurev-genom-083118-015306CrossRefGoogle ScholarPubMed
Hänselmann, A, Veltmann, C, Bauersachs, J, Berliner, D. Dilated cardiomyopathies and non-compaction cardiomyopathy. Herz 2020; 45: 212–220.10.1007/s00059-020-04903-5CrossRefGoogle ScholarPubMed
Hershberger, RE, Hedges, DJ, Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013; 10: 531.10.1038/nrcardio.2013.105CrossRefGoogle ScholarPubMed
Quiat, D, Witkowski, L, Zouk, H, Daly, KP, Roberts, AE. Retrospective analysis of clinical genetic testing in pediatric primary dilated cardiomyopathy: testing outcomes and the effects of variant reclassification. J Am Heart Assoc 2020; 9: e016195.10.1161/JAHA.120.016195CrossRefGoogle ScholarPubMed
Dong, X, Fan, P, Tian, T, et al. Recent advancements in the molecular genetics of left ventricular noncompaction cardiomyopathy. Clin Chim Acta 2017; 465: 40–44.10.1016/j.cca.2016.12.013CrossRefGoogle ScholarPubMed
Pignatelli, RH, McMahon, CJ, Dreyer, WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108: 2672–2678.10.1161/01.CIR.0000100664.10777.B8CrossRefGoogle ScholarPubMed
Oechslin, EN, Attenhofer Jost, CH, Rojas, JR, Kaufmann, PA, Jenni, R. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000; 36: 493–500.10.1016/S0735-1097(00)00755-5CrossRefGoogle ScholarPubMed
Shawky, RM, Elsayed, NS, Ibrahim, DS, Seifeldin, NS. Profile of genetic disorders prevalent in northeast region of Cairo, Egypt. Egypt J Med Hum Genet 2012; 13: 45–62.10.1016/j.ejmhg.2011.10.002CrossRefGoogle Scholar
Sobeih, AA, El-Saiedi, SA, Abdel Khalek, NS, Attia, SA, Hanna, BM. Parameters affecting outcome of paediatric cardiomyopathies in the intensive care unit: experience of an Egyptian tertiary centre over 7 years. Libyan J Med 2020; 15: 1822073.10.1080/19932820.2020.1822073CrossRefGoogle ScholarPubMed
Sabater-Molina, M, Pérez-Sánchez, I, Hernández del Rincón, JP, Gimeno, JR. Genetics of hypertrophic cardiomyopathy: a review of current state. Clin Genet 2018; 93: 3–14.10.1111/cge.13027CrossRefGoogle ScholarPubMed
Darwish, RK, Haghighi, A, Seliem, ZS, et al. Genetic study of pediatric hypertrophic cardiomyopathy in Egypt. Cardiol Young 2020; 30: 1910–1916.CrossRefGoogle ScholarPubMed
Miller, EM, Hinton, RB, Czosek, R, et al. Genetic testing in pediatric left ventricular noncompaction. Circ Cardiovasc Genet 2017; 10: e001735.10.1161/CIRCGENETICS.117.001735CrossRefGoogle ScholarPubMed
Yancy, CW, Jessup, M, Bozkurt, B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American college of cardiology foundation/American Heart Association task force on practice guidelines. Circulation 2013; 128: 1810–1852.10.1161/CIR.0b013e31829e8807CrossRefGoogle Scholar
Richardson, P, McKenna, RW, Bristow, M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task force on the definition and classification of cardiomyopathies. Circulation 1996; 93: 841–842.Google ScholarPubMed
Jenni, R, Oechslin, E, Schneider, J, Attenhofer Jost, C, Kaufmann, PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001; 86: 666–671.CrossRefGoogle ScholarPubMed
Poplin, R, Ruano-Rubio, V, DePristo, MA, et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv 2018: 201178. https://www.biorxiv.org/content/10.1101/201178v3.article-metrics 10.1101/201178CrossRefGoogle Scholar
Wang, K, Li, M, Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010; 38: e164.10.1093/nar/gkq603CrossRefGoogle ScholarPubMed
Aguib, Y, Allouba, M, Afify, A, et al. The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: defining a healthy volunteer cohort. NPJ Genomic Med 2020; 5: 46.10.1038/s41525-020-00153-wCrossRefGoogle ScholarPubMed
Scott, EM, Halees, A, Itan, Y, et al. Characterization of greater middle eastern genetic variation for enhanced disease gene discovery. Nat Genet 2016; 48: 1071–1079.10.1038/ng.3592CrossRefGoogle ScholarPubMed
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: 405–424.10.1038/gim.2015.30CrossRefGoogle ScholarPubMed
Doolan, A, Tebo, M, Ingles, J, et al. Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences. J Mol Cell Cardiol 2005; 38: 387–393.10.1016/j.yjmcc.2004.12.006CrossRefGoogle ScholarPubMed
Van Driest, SL, Ellsworth, EG, Ommen, SR, Tajik, AJ, Gersh, BJ, Ackerman, MJ. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation 2003; 108: 445–451.CrossRefGoogle Scholar
Walsh, R, Thomson, KL, Ware, JS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med 2017; 19: 192–203.10.1038/gim.2016.90CrossRefGoogle ScholarPubMed
Nguyen, S, Siu, R, Dewey, S, Cui, Z, Gomes, AV. Amino acid changes at arginine 204 of Troponin I result in increased calcium sensitivity of force development. Front Physiol 2016; 15: 520.Google Scholar
Gambarin, FI, Tagliani, M, Arbustini, E. Pure restrictive cardiomyopathy associated with cardiac troponin I gene mutation: mismatch between the lack of hypertrophy and the presence of disarray. Heart 2008; 94: 1257.10.1136/hrt.2008.154203CrossRefGoogle ScholarPubMed
Lu, C, Wu, W, Liu, F, et al. Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies. J Transl Med 2018; 16: 241.10.1186/s12967-018-1605-5CrossRefGoogle ScholarPubMed
Wang, C, Hata, Y, Hirono, K, et al. A wide and specific spectrum of genetic variants and genotype-phenotype correlations revealed by next-generation sequencing in patients with left ventricular noncompaction. J Am Heart Assoc 2017; 6: e006210.10.1161/JAHA.117.006210CrossRefGoogle ScholarPubMed
Dellefave, LM, Pytel, P, Mewborn, S, et al. Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation. Circ Cardiovasc Genet 2009; 2: 442–449.CrossRefGoogle ScholarPubMed
Farnaes, L, Hildreth, A, Sweeney, NM, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ genomic Med 2018; 3: 10.10.1038/s41525-018-0049-4CrossRefGoogle ScholarPubMed
Coppini, R, Ho, CY, Ashley, E, et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol 2014; 64: 2589–2600.10.1016/j.jacc.2014.09.059CrossRefGoogle ScholarPubMed
Burstein, DS, Gaynor, JW, Griffis, H, et al. Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. Pediatr Res 2020. https://www.nature.com/articles/s41390-020-1101-5 Google Scholar
Gigli, M, Begay, RL, Morea, G, et al. A review of the giant protein titin in clinical molecular diagnostics of cardiomyopathies. Front Cardiovasc Med 2016; 3: 21.CrossRefGoogle ScholarPubMed
Merlo, M, Sinagra, G, Carniel, E, et al. Poor prognosis of rare sarcomeric gene variants in patients with dilated cardiomyopathy. Clin Transl Sci 2013; 6: 424–428.10.1111/cts.12116CrossRefGoogle ScholarPubMed
Roberts, AM, Ware, JS, Herman, DS, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 2015; 7: 270ra6.CrossRefGoogle ScholarPubMed
Herman, DS, Lam, L, Taylor, MRG, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012; 366: 619–628.10.1056/NEJMoa1110186CrossRefGoogle ScholarPubMed
Towbin, JA. Pediatric primary dilated cardiomyopathy gene testing and variant reclassification: does it matter? J Am Hear Assoc 2020; 9: e016910.Google ScholarPubMed
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