rospedРоссийский педиатрический журнал имени М.Я. СтуденикинаM.Ya. Studenikin Russian Pediatric JournalФГАУ «НМИЦ здоровья детей» Минздрава России10.46563/1560-9561-2021-24-3-173-180gikigerosped-1198Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL INVESTIGATIONSЗначимость генетической верификации диагноза для детей с дилатационным фенотипом кардиомиопатии с некомпактным миокардом и повышенной трабекулярностьюThe significance of genetic verification of the diagnosis for children with a dilated phenotype of cardiomyopathy with non-compact myocardium and increased trabecularityСдвиговаНаталия АндреевнаSdvigovaNatalia A.

Врач-кардиолог ФГАУ «НМИЦ здоровья детей» Минздрава России

e-mail: sdvigova-natalya@yandex.ru

Cardiologist of the National Medical Research Center for Children’s Health, Moscow, 119991, Russian Federation

e-mail: sdvigova-natalya@yandex.ru

sdvigova-natalya@yandex.ruБасаргинаЕлена НиколаевнаBasarginaElena N.

Доктор мед. наук, проф., зав. отделением детской кардиологии ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruСавостьяновКирилл ВикторовичSavostyanovKirill V.

Канд. биол. наук, начальник Центра фундаментальных исследований в педиатрии ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruПушковАлександр АлексеевичPushkovAleksandr A.

Канд. биол. наук, вед. науч. сотр. лаб. молекулярной генетики и клеточной биологии, ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruЖароваОльга ПавловнаZharovaOlga P.

Врач — детский кардиолог, ФГАУ «НМИЦ здоровья детей» Минздрава России

noemail@neicon.ruФГАУ «Национальный медицинский исследовательский центр здоровья детей» Минздрава РоссииNational Medical Research Center for Children’s Health202110012025243173180Copyright © Сдвигова Н.А., Басаргина Е.Н., Савостьянов К.В., Пушков А.А., Жарова О.П., 20252025Сдвигова Н.А., Басаргина Е.Н., Савостьянов К.В., Пушков А.А., Жарова О.П.Sdvigova N.A., Basargina E.N., Savostyanov K.V., Pushkov A.A., Zharova O.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rosped.ru/jour/article/view/1198Цель

Цель: определить особенности течения дилатационного фенотипа кардиомиопатии с некомпактным миокардом и повышенной трабекулярностью, верифицировать молекулярно-генетический диагноз и установить сегрегацию нуклеотидных вариантов в семьях.

Материалы и методы

Материалы и методы. В исследование включено 50 пациентов, раcпределённых на 2 группы: 27 пациентов с дилатационным фенотипом кардиомиопатии и некомпактным миокардом и 23 пациента с дилатационным фенотипом и повышенной трабекулярностью. Проанализированы изменения лабораторных и инструментальных параметров, события и исходы. Применён метод массового параллельного секвенирования панели генов (81 ген). Для обработки данных использованы пакеты прикладных программ «SPSS Statistics 24.0», программное обеспечение «Alamut», база данных HGMD Professional.

Результаты

Результаты. Установлено, что через год терапии хронической сердечной недостаточности у больных с дилатационным фенотипом кардиомиопатии с повышенной трабекулярностью содержание концевого натрийуретического пептида в крови существенно уменьшилось. У пациентов обеих групп улучшилась сократительная способность миокарда и сократился конечно-диастолический размер левого желудочка. Значимые нуклеотидные варианты были верифицированы в 85% случаев у больных с некомпактным миокардом и у 91% у пациентов с повышенной трабекулярностью, при этом были выявлены предикторы неблагоприятного прогноза и тяжёлого течения кардиомиопатии — патогенные варианты c.2647G>A в гене MYH7, c.688G>A в гене TPM1, c.2350C>T в гене CACNA1C. Обследованы 18 семей, выявлены 3 мутации de novo, что подтверждает высокую частоту бессимптомных и малосимптомных носителей нуклеотидных вариантов в семьях.

Заключение

Заключение. Определение молекулярно-генетической причины дилатационного фенотипа кардиомиопатии позволяет оптимизировать тактику ведения больных детей, а выявление семейной сегрегации мутаций с определением носителей обеспечивает своевременное наблюдение специалистов.

Участие авторов

Участие авторов: Сдвигова Н.А., Басаргина Е.Н., Савостьянов К.В. — концепция и дизайн исследования; Сдвигова Н.А., Басаргина Е.Н., Савостьянов К.В., Пушков А.А. — сбор и обработка материала; Сдвигова Н.А. — статистическая обработка, написание текста; Басаргина Е.Н., Савостьянов К.В., Пушков А.А., Жарова О.П. — редактирование. Все соавторы — утверждение окончательного варианта статьи, ответственность за целостность всех частей статьи.

Финансирование

Финансирование. Работа не имеет финансовой поддержки.

Конфликт интересов

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Информированное согласие

Информированное согласие. От родителей пациентов получено письменное добровольное информированное согласие на участие в исследовании.

Поступила 20

Поступила 20.05.2021Принята к печати 23.06.2021Опубликована 16.07.2021

Purpose

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

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

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

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.

Contribution

Contribution: Sdvigova N.A., Basargina E.N., Savostyanov K.V. — concept and design of the study; Sdvigova N.A., Basargina E.N., Savostyanov K.V., Pushkov A.A. — collection and processing of material; Sdvigova N.A. — statistical processing, text writing; Basargina E.N., Savostyanov K.V., Pushkov A.A., Zharova O.P. — text editing. All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgement

Acknowledgement.  The study had no financial support

Conflict of interest

Conflict of interest. Authors declared no conflict of interest.

Informed consent

Informed consent: informed consent was received from the patients’ parents for the participation of a study.

Received

Received: May 20, 2021Accepted: June 23, 2021Published: July 16, 2021

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The authors declare that there are no conflicts of interest present.