danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"dan-423Research ArticleБИОЛОГИЯBIOLOGYДИАГНОСТИКА БОЛЕЗНИ ДАНОНА МЕТОДОМ TARGETED NEXT-GENERATION SEQUENCING: ИДЕНТИФИКАЦИЯ МУТАЦИИ В ГЕНЕ LAMP2DANON DISEASE DIAGNOSIS BY TARGETED NEXT-GENERATION SEQUENCING: IDENTIFICATION OF LAMP2 MUTATIONSСивицкаяЛ. Н.SivitskayaL. N.

канд. биол. наук, ст. науч. сотрудник

h. D. (Biology), Senior researcher

silarissa@yandex.ruДаниленкоН. Г.DanilenkoN. G.

канд. биол. наук, вед. науч. сотрудник

Ph. D. (Biology), Leading researcher

cytoplasmic@mail.ruВайханскаяТ. Г.VaikhanskayaT. G.

канд. мед. наук, вед. науч. сотрудник

Ph. D. (Medicine), Leading researcher

tat_vaikh@mail.ruЛевданскийО. Д.LiaudanskiA. D.

канд. биол. наук, науч. сотрудник

Ph. D. (Biology), Researcher

cytoplasmic@mail.ruДавыденкоО. Г.DavydenkoO. G.

член-корреспондент, д-р биол. наук, заведующий лабораторией

Corresponding Member, D. Sc. (Biology), Head of the Laboratory

davydenko@tut.byИнститут генетики и цитологии Национальной академии наук БеларусиInstitute of Genetics and Cytology of the National Academy of Sciences of BelarusРеспубликанский научно-практический центр «Кардиология»Republican Scientific and Practical Center of Cardiology2017150820176136472Copyright © Сивицкая Л.Н., Даниленко Н.Г., Вайханская Т.Г., Левданский О.Д., Давыденко О.Г., 20172017Сивицкая Л.Н., Даниленко Н.Г., Вайханская Т.Г., Левданский О.Д., Давыденко О.Г.Sivitskaya L.N., Danilenko N.G., Vaikhanskaya T.G., Liaudanski A.D., Davydenko O.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/423

В сообщении представлен клинический случай болезни Данона, впервые диагностированной в Беларуси. Метод targeted Next-Generation Sequencing (tNGS) был применен для поиска изменений в 46 генах, ассоциированных с развитием кардиомиопатий различного генеза, у пациента с дилатационной кардиомиопатией. Сопутствующими клиническими проявлениями были периферические мышечные нарушения и умеренная деменция. Выявлена гемизиготная делеция с.864+3_864+6delGAGT (rs397516751, NM_002294.2) в гене LAMP2, затрагивающая естественный сайт сплайсинга. Ген LAMP2 (Lysosomal Associated Membrane Protein 2, Xq24) кодирует мембранный гликопротеид, необходимый для адгезии лизосом. Мутации в нем приводят к накоплению гликогена в клетках вследствие нарушения процесса аутофагии лизосомами. Клинически они проявляются болезнью Данона: гипертрофическая или дилатационная кардиомиопатия, скелетная миопатия и умственная отсталость. В представленном клиническом случае метаболическая причина кардиомиопатии была не распознана. Метод tNGS позволил скорректировать диагноз. Очевидна необходимость наиболее ранней постановки правильного диагноза у таких пациентов для своевременного принятия мер, направленных на замедление прогрессирования заболевания. Болезнь Данона может протекать бессимптомно до пубертатного возраста, далее происходит стремительное развитие и прогрессирование признаков с высокой смертностью, возникающей внезапно.

The case report of the Danon disease firstly diagnosed in Belarus is presented. The targeted Next-Generation Sequencing (tNGS) was used to search for mutations in 46 genes associated with cardiomyopathy of different genesis in a patient suffered from dilated cardiomyopathy, peripheral muscle disorders and mild dementia. Hemizygous deletion c.864+3_864+6delGAGT (rs397516751, NM_002294.2) in the LAMP2 gene affecting the natural splice site was detected. The LAMP2 gene (Lysosomal Associated Membrane Protein 2, Xq24) encodes a membrane glycoprotein essential for the adhesion of lysosomes. Mutations in LAMP2 lead to the distortion of the autophagy by lysosomes and glycogen accumulation in the cells. Clinically, they manifest in the Danon disease: hypertrophic or dilated cardiomyopathy, skeletal myopathy, and mental retardation. The metabolic reason of cardiomyopathy has not been recognized in the present case. The tNGS has allowed one to correct the diagnosis. The early exact diagnosis for such patients is essential to slow down the disease progression. The Danon disease can proceed asymptomatically before puberty and then develops rapidly with sudden mortality. 

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