THE SIGNIFICANCE OF GENETIC VERIFICATION OF THE DIAGNOSIS FOR CHILDREN WITH A DILATED PHENOTYPE OF CARDIOMYOPATHY WITH NON-COMPACT MYOCARDIUM AND INCREASED TRABECULARITY

Purpose: to compare the course of the disease in the dilated phenotype of cardiomyopathy with a non-compact myocardium and increased trabecularity, verify the molecular genetic diagnosis using the new generation sequencing method, and study the segregation of nucleotide variants in families. Materials and methods. The study included 50 patients, divided into two groups: 27 patients with a dilated phenotype of cardiomyopathy and non-compact myocardium and 23 patients with a dilated phenotype and increased trabecularity. Changes in the laboratory and instrumental parameters, events and outcomes were analyzed. The massively parallel sequencing of a panel of genes developed at the National Medical Research Center of Children’s Health of the Ministry of Health of the Russian Federation (81 genes) was applied. For data processing, the IBM SPSS Statistics 24.0 application package was used for bioinformatic analysis and assessment of the pathogenicity of the identified nucleotide variants, the Russian guidelines for interpreting human DNA nucleotide data, Alamut software and the HGMD Professional database were used. Results. Following a year of therapy for chronic heart failure in DF CMP patients, the content of terminal natriuretic peptide in the blood of patients with increased trabecularity was found to decline significantly. In patients in both groups, myocardial contractility improved and left ventricular end-diastolic size decreased. Significant nucleotide variants when using the cardiopanel were verified in 85% of cases in patients with non-compact myocardium and 91% in patients with increased trabecularity. At the same time, predictors of poor prognosis and severe course of cardiomyopathy were identified - pathogenic variants c.2647G>A in the MYH7 gene, c.688G>A in the TPM1 gene, c.2350C> T in the CACNA1C gene. In one clinical case, when laminopathy was detected, a cardioverter-defibrillator was installed as prophylaxis for sudden death. In addition, 18 families were examined, 3 cases of de novo mutation were identified, confirming the high frequency of asymptomatic and low-symptom carriers of nucleotide variants. Conclusion. The determination of the molecular and genetic cause of the dilated cardiomyopathy phenotype allows optimizing the management tactics of sick children. Furthermore, the identification of family segregation of mutations with the identification of carriers ensures timely monitoring by specialists.

Савостьянов К.В., Намазова-Баранова Л.С., Басаргина Е.Н., Вашакмадзе Н.Д., Журкова Н.В., Пушков А.А. и др. Новые варианты генома российский детей с генетически обусловленными кардиомиопатиями, выявленные методом массового параллельного секвенирования. Вестник Российской академии медицинских наук. 2017; 72(4): 242-53. https://doi.org/10.15690/vramn872

Jefferies J.L., Wilkinson J.D., Sleeper L.A., Colan S.D., Lu M., Pahl E., et al. Pediatric cardiomyopathy registry investigators. Cardiomyopathy phenotypes and outcomes for children with left ventricular myocardial noncompaction: results from the pediatric cardiomyopathy registry. J. Card. 2015; 21(11): 877-84. https://doi.org/10.1016/j.cardfail.2015.06.381

Wengrofsky P., Armenia C., Oleszak F., Kupferstein E., Rednam C., Mitre C.A., et al. Left ventricular trabeculation and noncompaction cardiomyopathy: a review. EC Clin. Exp. Anat. 2019; 2(6): 267-83.

Xing I., Ichida F., Matsuoka T., Isobe T., Ikemoto Y., Higaki T., et al. Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity. Mol. Genet. Metab. 2006; 88(1): 71-7. https://doi.org/10.1016/j.ymgme.2005.11.009

Hershberger R.E., Givertz M.M., Ho C.Y., Judge D.P., Kantor P.F., McBride K.L., et al. Genetic evaluation of cardiomyopathy - a heart failure society of America practice guideline. J. Card. Fail. 2018; 24(5): 281-302. https://doi.org/10.1016/j.cardfail.2018.03.004

Рыжкова О.П., Кардымон О.Л., Прохорчук Е.Б., Коновалов Ф.А., Масленников А.Б., Степанов В.А. и др. Руководство по интерпретации данных последовательности ДНК человека, полученных методами массового параллельного секвенирования (MPS) (редакция 2018, версия 2). Медицинская генетика. 2019; 18(2): 3-23. https://doi.org/10.25557/2073-7998.2019.02.3-23

Waddell-Smith K.E., Donoghue T., Oates S., Graham A., Crawford J., Stiles M.K., et al. Inpatient detection of cardiac-inherited disease: the impact of improving family history taking. Open Heart. 2016; 3(1): e000329. https://doi.org/10.1136/openhrt-2015-000329

Teirlinck C.H., Senni F., Malti R.E., Majoor-Krakauer D., Fellmann F., Millat G., et al. A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death. BMC Med. Genet. 2012; 13: 105. https://doi.org/10.1186/1471-2350-13-105

Kelly M.A., Caleshu C., Morales A., Buchan J., Wolf Z., Harrison S.M., et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s inherited cardiomyopathy expert panel. Genet. Med. 2018; 20(3): 351-9. https://doi.org/10.1038/gim.2017.218

Hayashi T., Arimura T., Itoh-Satoh M., Ueda K., Hohda S., Inagaki N., et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J. Am. Coll. Cardiol. 2004; 44(11): 2192-201. https://doi.org/10.1016/j.jacc.2004.08.058

Nykamp K., Anderson M., Powers M., Garcia J., Herrera B., Ho Y.Y., et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet. Med. 2017; 19(10): 1105-17. https://doi.org/10.1038/gim.2017.37

Skinner J.R., Crawford J., Smith W., Aitken A., Heaven D., Evans C.A., et al. Prospective, population-based long QT molecular autopsy study of postmortem negative sudden death in 1 to 40 years old. Heart Rhythm. 2011; 8(3): 412-9. https://doi.org/10.1016/j.hrthm.2010.11.016

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(5): 405-24. https://doi.org/10.1038/gim.2015.30

Tian T., Wang J., Wang H., Sun K., Wang Y., Jia L., et al. A low prevalence of sarcomeric gene variants in a Chinese cohort with left ventricular non-compaction. Heart Vessels. 2015; 30(2): 258-64. https://doi.org/10.1007/s00380-014-0503-x

Gajendrarao P., Krishnamoorthy N., Kassem H.Sh., Moharem-Elgamal S., Cecchi F., Olivotto I., et al. Molecular modeling of disease causing mutations in domain C1 of cMyBPC3. PLoS One. 2013; 8(3): e59206. https://doi.org/10.1371/journal.pone.0059206

Kostareva A., Kiselev A., Gudkova A., Frishman G., Ruepp A., Frishman D., et al. Genetic spectrum of idiopathic restrictive cardiomyopathy uncovered by next-generation sequencing. PLoS One. 2016; 11(9): e0163362. https://doi.org/10.1371/journal.pone.0163362

Сдвигова Н.А., Басаргина Е.Н., Рябцев Д.В., Савостьянов К.В., Пушков А.А., Журкова Н.В. и др. Актуальность генетической верификации некомпактной кардиомиопатии у детей: клинические случаи. Вопросы современной педиатрии. 2018; 17(2): 157-65. https://doi.org/10.15690/vsp.v17i2.1883

Herman D.S., Lam L., Taylor M.R., Wang L., Teekakirikul P., Christodoulou D., et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 2012; 366(7): 619-28. https://doi.org/10.1056/NEJMoa1110186

Lakdawala N.K., Dellefave L., Redwood C.S., Sparks E., Cirino A.L., Depalma S., et al. Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy. J. Am. Coll. Cardiol. 2010; 55(4): 320-9. https://doi.org/10.1016/j.jacc.2009.11.017

Tóth T., Nagy V., Faludi R., Csanády M., Nemes A., Simor T., et al. The Gln1233ter mutation of the myosin binding protein C gene: causative mutation or innocent polymorphism in patients with hypertrophic cardiomyopathy? Int. J. Cardiol. 2011; 153(2): 216-9. https://doi.org/10.1016/j.ijcard.2011.09.062

Walsh R., Thomson K.L., Ware J.S., Funke B.H., Woodley J., McGuire K.J., et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet. Med. 2016; 19(2): 192-203. https://doi.org/10.1038/gim.2016.90

Hoedemaekers Y.M., Caliskan K., Michels M., Frohn-Mulder I., van der Smagt J.J., Phefferkorn J.E., et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ. Cardiovasc. Genet. 2010; 3(3): 232. https://doi.org/10.1161/circgenetics.109.903898

Roncarati R., Latronico M.V., Musumeci B., Aurino S., Torella A., Bang M.L., et al. Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy. J. Cell. Physiol. 2011; 226(11): 2894-900. https://doi.org/10.1002/jcp.22636

Beggali A., Bollen I.A., Rasmussen T.B., van den Hoogenhof M.M., van Deutekom H.W., Schafer S., et al. A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. Cardiovasc. Res. 2016; 112(1): 452-63. https://doi.org/10.1093/cvr/cvw192

Kapplinger J.D., Tester D.J., 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(1): 33-46. https://doi.org/10.1016/j.hrthm.2009.09.069

Li D., Czernuszewicz G.Z., Gonzalez O., Tapscott T., Karibe A., Durand J.B., et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001; 104(18): 2188-93. https://doi.org/10.1161/hc4301.098285

Ichida F., Hamamichi Y., Miyawaki T., Ono Y., Kamiya T., Akagi T., et al. Clinical features of isolated noncompaction of the ventricular myocardium. Long-term clinical course, hemodynamic properties, and genetic background. J. Am. Coll. Cardiol. 1999; 34(1): 233-40. https://doi.org/10.1016/s0735-1097(99)00170-9

Brescia S.T., Rossano J.W., Pignatelli R., Jefferies J.L., Price J.F., Decker J.A., et al. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation. 2013; 127(22): 2202-8. https://doi.org/10.1161/circulationaha.113.002511

Miszalski-Jamka K., Jefferies J.L., Mazur W., Głowacki J., Hu J., Lazar M., et al. Novel Genetic triggers and genotype-phenotype correlations in patients with left ventricular noncompaction. Circ. Cardiovasc. Genet. 2017; 10(4): e001763. https://doi.org/10.1161/circgenetics.117.001763

Nouhravesh N., Ahlberg G., Ghouse J., Andreasen C., Svendsen J. H., Haunsø S., et al. Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy. Mol. Genet. Genomic. Med. 2016; 4(6): 617-23. https://doi.org/10.1002/mgg3.245