vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2022-19-1-48-61vestim-821Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEКлинические и молекулярно-генетические характеристики классической гомоцистинурииClinical and molecular genetic characteristics of classical homocystinuriaГусинаА. А.GusinaA. A.

Гусина Ася Александровна - кандидат медицинских наук, заведующий лабораторией.

ул. Орловская, 66, 220053, Минск.

Asya A. Gusina - Ph. D. (Med.), Head of the Laboratory, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

asya.gusina@mail.ruЗиновикА. В.ZinovikA. V.

Зиновик Александр Валентинович - заведующий лабораторией.

ул. Орловская, 66, 220053, Минск.

Aliaksandr V. Zinovik - Head of the Laboratory, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

alizi@yandex.ruНаумчикИ. В.NaumchikI. N.

Наумчик Ирина Всеволодовна - кандидат медицинских наук, заместитель директора по медицинской генетике.

ул. Орловская, 66, 220053, Минск.

Irina V. Naumchik - Ph. D. (Med.), Deputy Director for Medical Genetics, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

belgenetics@yahoo.comКулакВ. Д.KulakV. D.

Кулак Виктория Дмитриевна - врач-генетик.

ул. Орловская, 66, 220053, Минск.

Victoria D. Kulak – geneticist, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

kulak.vd@mail.ruМотюкИ. Н.MotiukI. N.

Мотюк Ирина Николаевна - врач-генетик, главный внештатный специалист по медицинской генетике главного управления здравоохранения Гродненского областного исполнительного комитета.

ул. Горького, 77, 230009, Гродно.

Irina N. Motiuk - geneticist, Chief Freelance Specialist in Medical Genetics of the Main Health Department of the Grodno Regional Executive Committee, Grodno Regional Clinical Perinatal Center.

77, Gorky Str., 230009, Grodno.

imotyuk@mail.ruБойшаА. С.BoishaA. S.

Бойша Анна Станиславовна - врач-генетик.

ул. Первомайская, 59а, 212030, Могилев.

Anna S. Boisha – geneticist, Mogilev Regional Treatment and Diagnostic Center.

59a, Pervomayskaya Str., 212030, Mogilev.

gen@modc.byМясниковС. О.MiasnikovS. O.

Мясников Святослав Олегович - врач лабораторной диагностики.

ул. Орловская, 66, 220053, Минск.

Sviatoslav O. Miasnikov - doctor of laboratory diagnostics, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

svyatoslavm@bk.ruСталыбкоА. С.StalybkoN. S.

Сталыбко Анастасия Сергеевна - младший научный сотрудник.

ул. Орловская, 66, 220053, Минск.

Nastya S. Stalybko - Junior Researcher, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

nastyastalybko@gmail.comГусинаН. Б.GusinaN. B.

Гусина Нина Борисовна - кандидат биологических наук, врач лабораторной диагностики.

ул. Орловская, 66, 220053, Минск.

Nina B. Gusina - Ph. D. (Biol.), doctor of laboratory diagnostics, Republican Scientific Practical Centre “Mother and child”.

66, Orlovskaya Str., 220053, Minsk.

nina.gusina@tut.byРеспубликанский научно-практический центр «Мать и дитя»Republican Scientific Practical Centre «Mother and child»Гродненский областной клинический перинатальный центрGrodno Regional Clinical Perinatal CenterМогилевский областной лечебно-диагностический центрMogilev Regional Treatment and Diagnostic Center2022100320221914861Copyright © Гусина А.А., Зиновик А.В., Наумчик И.В., Кулак В.Д., Мотюк И.Н., Бойша А.С., Мясников С.О., Сталыбко А.С., Гусина Н.Б., 20222022Гусина А.А., Зиновик А.В., Наумчик И.В., Кулак В.Д., Мотюк И.Н., Бойша А.С., Мясников С.О., Сталыбко А.С., Гусина Н.Б.Gusina A.A., Zinovik A.V., Naumchik I.N., Kulak V.D., Motiuk I.N., Boisha A.S., Miasnikov S.O., Stalybko N.S., Gusina N.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/821

Классическая гомоцистинурия - аутосомно-рецессивное заболевание, обусловленное дефицитом активности цистатионин-в-синтазы, возникающим вследствие мутаций в гене CBS.

Цель исследования - определить особенности клинических проявлений и установить мутации в гене CBS у пациентов с классической гомоцистинурией в Республике Беларусь.

В исследуемую группу были включены пациенты с классической гомоцистинурией и их здоровые сибсы (3 пробанда и 2 сибса) из трех неродственных семей. Диагноз классической гомоцистинурии пробандам был установлен на основании количественного определения концентрации общего гомоцистеина. Поиск мутаций в гене CBS осуществлен с помощью высокопроизводительного секвенирования. Наличие выявленных вариантов у пробандов и их сибсов было подтверждено секвенированием по Сэнгеру.

У всех обследованных пробандов выявлены характерные клинические признаки классической гомоцистинурии: врожденное смещение хрусталиков, изменения со стороны скелета. У 2 из 3 пробандов были отмечены симптомы поражения нервной системы, в том числе задержка развития и умственная отсталость, судороги, психические нарушения.

У пробанда 1 выявлена миссенс-мутация c.430G>C (p.Glu144Gln, rs121964966) в гомозиготном состоянии. Пробанд 2 являлся гомозиготным носителем замены c.473C>T p.(Ala158Val, rs1376851289). У пробанда 3 обнаружен миссенс-вариант c.1064C>T p.(Ala355Val, rs772384826). Сибсы пробандов 1 и 3 являлись носителями соответствующих мутаций в гетерозиготном состоянии.

Классическая гомоцистинурия - весьма редкое заболевание в Республике Беларусь. Все случаи заболеваемости в Беларуси обусловлены очень редкими мутациями, не зарегистрированными в граничащих с республикой странах, и являются следствием браков между родственниками или уроженцами одной местности. Нами впервые описаны фенотипические проявления мутаций p.Glu144Gln и p.Ala355Val, расширено описание спектра клинических проявлений замены Ala158Val, проведена оценка клинической значимости выявленных вариантов в соответствии с современными критериями.

Classical homocystinuria is caused by a genetic mutation in the CBS gene, which leads to low levels or absence of an enzyme called cystathionine beta-synthase.

The purpose of the study was to analyze the clinical features and molecular and genetic data of patients with classical homocystinuria in Belarus.

The study group included patients with classical homocystinuria and their healthy siblings (3 probands and 2 siblings) from three unrelated families. Diagnosis of homocystinuria was made on a quantitative determination of the total homocysteine level in plasma. The next-generation sequencing was performed for the molecular genetic analysis of the CBS gene. The presence of the identified variants in probands and their siblings was confirmed by the Sanger sequencing.

All probands had specific clinical signs of classic homocystinuria: ectopia lentis, skeletal pathology, intellectual, psychiatric, behavioural problems and seizures (in 2 of 3 probands).

Homozygous missense-mutations c.430G>C (p.Glu144Gln, rs121964966), c.473C>T p.(Ala158Val, rs1376851289) and 1064C>T p.(Ala355Val, rs772384826) were identified in proband 1, 2 and 3 respectively. Healthy siblings of probands 1 and 3 were the heterozygous carriers of the corresponding mutations.

Classical homocystinuria is a very rare disease in the Republic of Belarus. All cases of the disease in Belarus are caused by very rare mutations not registered in the neighboring countries and are the result of marriages between the relatives or the natives of the same area. We have described for the first time the phenotypic manifestations of the p.Glu144Gln and p.Ala355Val mutations, expanded the description of the spectrum of clinical manifestations of the Ala158Val substitution, and assessed the clinical significance of the identified variants in accordance with the modern criteria.

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