Окулофарингеальная миодистрофия (ОФМД) - наследственное нервно-мышечное заболевание c аутосомно-доминантным и редко - с аутосомно-рецессивным типом наследования. В работе исследованы 50 больных с клиническим диагнозом ОФМД, 23 пресимптоматических носителя мутации из 45 неродственных семей и 56 здоровых родственников, а также популяционные выборки из четырех этнических групп Якутии: якуты, эвены, эвенки, юкагиры. Установлено, что причиной развития ОФМД во всех исследованных семьях является одинаковое увеличение GCN-повторов в гене PABPN1 до 14 копий. Мутантный аллель имеет структуру: (GCN)14 - (GCG)10(GCA)3GCG. В локусе ОФМД исследована генетическая вариабельность по 10 SNPs в семьях больных и в популяционных выборках. Методом сегрегационного анализа и с использованием ЕМ-алгоритма установлены гаплотипы локуса ОФМД в группах больных, у носителей мутации и в популяционных выборках. У якутов и русских, больных и носителей мутации ОФМД, обнаружен только один гаплотип по четырем SNPs (ATCG), сцепленный с мутантным аллелем (GCN)14. Вероятно, это свидетельствует о накоплении мутации в результате эффекта основателя.

The discovery of cell-free DNA in blastocoele fluid opens new perspectives for the development of preimplantation genetic diagnosis of human chromosomal and genetic diseases. In this review we analyzed the results of the first studies, which made it possible to evaluate the effectiveness of the application of a new source of biological material and showed a high degree of agreement between the results of molecular karyotyping with cell-free DNA and blastocyst cells. The results suggest the possibility of developing a noninvasive method of preimplantation genetic diagnosis, which may open a new round of progress in the field of assisted reproductive technologies and the genetics of early stages of human ontogenesis.

Обнаружение внеклеточной ДНК в полости ранней бластоцисты открывает новые перспективы в развитии преимплантационной генетической диагностики хромосомных и наследственных болезней человека. В настоящем обзоре проанализированы итоги первых исследований, позволивших оценить эффективность использования нового источника биологического материала, а также продемонстрировавших высокую степень совпадения результатов молекулярного кариотипирования с применением фракции внеклеточной ДНК и клеток самой бластоцисты. Полученные данные свидетельствуют о возможности разработки метода преимплантационной генетической диагностики на основе бластоцентеза, который может открыть новый виток прогресса в области вспомогательных репродуктивных технологий и в изучении генетики ранних этапов онтогенеза человека.

Regulatory single nucleotide polymorphisms (rSNPs) are the least-studied group of SNP; however, they play an essential role in the development of human pathology by altering the level of candidate genes expression. In this work, we analyzed 29 rSNPs in 17 new candidate genes associated with preeclampsia (PE) according to the analysis of the transcriptome in placental tissue. Three ethnic groups have been studied (Yakut, Russian, and Buryat). We have detected significant associations of PE with eight rSNPs in six differentially expressed genes, i.e., rs10423795 in the LHB gene; rs3771787 in the HK2 gene; rs72959687 in the INHA gene; rs12678229, rs2227262, and rs3802252 in the NDRG1 gene; rs34845949 in the SASH1 gene; and rs66707428 in the PPP1R12C gene. We used a new approach to detecting genetic markers of multifactorial diseases in the case of PE based on a combination of genomic, transcriptomic, and bioinformatic approaches. This approach proved its efficiency and may be applied to detecting new potential genetic markers in genes involved in disease pathogenesis, which reduces missing heritability in multifactorial diseases.

Однонуклеотидные полиморфизмы (SNP), расположенные в регуляторных участках генов, относятся к наименее изученной функциональной группе SNP. Однако, изменяя уровень экспрессии генов, они играют значимую роль в развитии различных патологических состояний человека. В представленной работе рассмотрены 29 регуляторных SNP (rSNP) в 17 генах, ассоциированных, по данным анализа транскриптома плацентарной ткани, с развитием преэклампсии. В исследовании, выполненном в трех этнических группах (русские, якуты и буряты), получены данные, свидетельствующие об ассоциации с преэклампсией восьми rSNP в шести дифференциально экспрессирующихся генах: rs10423795 гена LHB, rs3771787 гена HK2, rs72959687 гена INHA, rs34845949 гена SASH1, rs2227262, rs3802252, rs12678229 гена NDRG1 и rs66707428 гена PPP1R12C. На примере преэклампсии проведен поиск генетических маркеров многофакторных заболеваний, основанный на комбинации геномных, транскриптомных и биоинформатических методов. Этот подход показал свою эффективность и может быть использован для обнаружения новых потенциальных патогенетических маркеров, уменьшая долю “упущенной наследуемости” при многофакторных болезнях.

Human genetic markers linked with the X chromosome (X-linked) are used in the field of population and medical genetics, as well as for DNA identification of individuals in forensic science and forensic medicine. We proposed an XSNPid panel that consists of 66 unlinked single nucleotide X chromosome markers and developed a protocol for their multiplex genotyping using multilocus PCR and MALDI-TOF mass spectrometry. The XSNPid panel is genotyped within two multiplexes (36 and 30 markers). The developed protocol provides an efficient genotype reading; the fraction of determined genotypes is 98.29%. The high level of gene diversity (0.461) for the X-linked SNPs included in the panel is characteristic of the Russian population. A total of 63 out of 66 markers that provide a high efficiency of genotyping and independent inheritance are suitable for DNA identification purposes. The XSNPid panel is characterized by a very high discriminating ability when studying the Russian population. The probability of genotype coincidence in two unrelated individuals is 9 × 10–27 for women and 2 × 10–18 for men. Also, the XSNPid panel has a greater multiplex capacity in addition to a higher discriminating ability compared to the other closest analogues of the X chromosome SNP sets, which makes it more cost effective and less time consuming. The XSNPid panel is a convenient tool, not only for individual DNA identification, but also for population genetic studies.

Генетические маркеры человека, сцепленные с X-хромосомой (кратко – X-сцепленные), применяются в области популяционной генетики, медицинской генетики, а также для ДНК-идентификации индивида в криминалистике и судебной медицине. Нами предложена панель XSNPid, состоящая из 66 несцепленных однонуклеотидных маркеров Х-хромосомы, и разработан протокол их мультиплексного генотипирования с помощью методов многолокусной ПЦР и масс-спектрометрии MALDI-TOF. Панель XSNPid генотипируется в составе двух мультиплексов (на 36 и 30 маркеров). Разработанный протокол обеспечивает эффективное чтение генотипов: доля определяемых генотипов составляет 98.29%. Для русской популяции характерен высокий уровень генного разнообразия (0.461) по X-сцепленным SNP, включенным в панель. 63 из 66 маркеров, обеспечивающих высокую эффективность генотипирования и независимое наследование, пригодны для целей ДНК-идентификации. Для панели XSNPid характерна очень высокая дискриминационная способность при исследовании русской популяции. Вероятность совпадения генотипов у двух неродственных индивидов составляет 9 × 10–27 для женщин и 2 × 10–18 для мужчин. При сравнении с другими ближайшими аналогами наборов X-хромосомных SNP, панель XSNPid обладает, кроме более высокой дискриминирующей способности, также большей емкостью мультиплексов, что делает ее более экономически выгодной и требует меньших затрат времени при использовании. Панель XSNPid – удобный инструмент не только для индивидуальной ДНК-идентификации, но и для популяционно-генетических исследований.

A group of patients with ischemic heart disease and myocardial infarction (N = 156) and a reference population sample (N = 300) were genotyped for 58 single nucleotide polymorphisms (SNPs) in the genes involved in extracellular matrix function and collagen metabolism or associated with cardiovascular diseases and atherosclerotic plaque stability. Genotyping was performed by mass-spectrometry with two multiplex sets of 27 and 31 SNPs. The study revealed different genetic composition of predisposition to cardiovascular disease continuum (CVDC) syntropy (patients with concomitant conditions: hypercholesterolemia, hypertension, and type-II diabetes mellitus, N = 96) and to isolated myocardial infarction (without these conditions, N = 60). Only the KIAA1462 gene (rs3739998) showed associations with both CVDC syntropy (OR = 1.71; 95% CI 1.19–2.45; р = 0.003) and isolated infarction (OR = 1.58; 95% CI 1.05–2.40; р = 0.028). Isolated myocardial infarction was also associated with LIG1 (rs20579) (OR = 2.08; 95% CI 1.06–4.17; р = 0.028) and ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07–2.50; р = 0.020). CVDC syntropy was associated with CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03–2.12; р = 0.029) and APOA2 (rs5082) (OR = 1.47; 95% CI 1.02–2.11; р = 0.035). So, genes involved in fibrogenesis contribute to predisposition to the myocardial infarction as well. Isolated myocardial infarction and CVDC syntropy can be considered as pathogenetically different cardiovascular conditions, with different genes that contribute to the susceptibility.

В группе больных с ишемической болезнью сердца и инфарктом миокарда (N = 156), а также в популяционной выборке (N = 300) изучены 58 однонуклеотидных замен (SNP) в генах, вовлеченных в функционирование внеклеточноего матрикса, в метаболизм коллагена или ассоциированных с болезнями сердечно-сосудистого континуума и стабильностью атеросклеротической бляшки. Генотипирование выполняли при помощи масс-спектрометрии (две мультиплексные панели, включающие 27 и 31 SNP). В подгруппе больных с “синтропией сердечно-сосудистого континуума” (инфаркт миокарда с несколькими сопутствующими заболеваниями, такими, как артериальная гипертония, сахарный диабет типа 2 и гиперхолестеринемия, 96 человек) и в подгруппе с “изолированным” инфарктом миокарда (в отсутствие всех указанных заболеваний, 60 человек) “структура” генетической предрасположенности к этим двум формам течения ишемической болезни сердца различна. Показано, что только ген KIAA1462 (rs3739998) ассоциациирован как с “изолированным” инфарктом миокарда (OR = 1.58; 95% CI 1.05–2.40; р = 0.028), так и с сочетанной формой патологии (OR = 1.71; 95% CI 1.19–2.45; р = 0.003). С “изолированным” инфарктом миокарда ассоциированы также гены LIG1 (rs20579) (OR = 2.08; 95% CI 1.06–4.17; р = 0.028) и ADAMDEC1 (rs3765124) (OR = 1.63; 95% CI 1.07–2.50; р = 0.020). С синтропией сердечно-сосудистого континуума ассоциированы гены CDKN2BAS1 (rs1333049) (OR = 1.48; 95% CI 1.03–2.12; р = 0.029) и APOA2 (rs5082) (OR = 1.47; 95% CI 1.02–2.11; р = 0.035). Таким образом, установлено, что гены, участвующие в процессах фиброгенеза, вносят свой вклад в развитие предрасположенности к инфаркту миокарда. Синтропию сердечно-сосудистого континуума и “изолированный” инфаркт миокарда можно рассматривать как патогенетически обособленные формы сердечно-сосудистых заболеваний, подверженность которым определяется генами различных функциональных классов

Tuberculosis (TB) is a common infectious disease caused by M. tuberculosis. The risk of the disease is dependent on complex interactions between host genetics and environmental factors. Accumulated genomic data, along with novel methodological approaches such as associative networks, facilitate studies into the inherited basis of TB. In the current study, we carried out the reconstruction and analysis of an associative network representing molecular interactions between proteins and genes associated with TB. The network predominantly comprises of well-studied key proteins and genes which are able to govern the immune response against M. tuberculosis. However, this approach also allowed us to reveal 12 proteins encoded by genes, the polymorphisms of which have never been studied in relation to M. tuberculosis infection. These proteins include surface antigens (CD4, CD69, CD79, CD80, MUC16) and other important components of the immune response, inflammation, pathogen recognition, cell migration and activation (HCST, ADA, CP, SPP1, CXCR4, AGER, PACRG). Thus, the associative network approach enables the discovery of new candidate genes for TB susceptibility.

Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars-a Slavic-speaking Sunni-Muslim minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y-chromosomal, mitochondrial and autosomal DNA variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China.

Tuberculosis is a global pressing healthcare issue in the modern world. Host genetics is an important modifier of the disease risk. Genetic and genomic studies aim to reveal key inherited variants of the human genome associated with the susceptibility to tuberculosis. Much attention is given to the study of differential genetic susceptibility to various stages of tuberculous infection, particularly latent tuberculosis, the detection of which is most challenging. Susceptibility genes have been identified and most of which exhibit a relatively small effect on the disease risk. On the other hand, a proportion of children suffer from Mendelian susceptibility to tuberculosis associated with rare mutations with deterministic effect in genes for the components of cellular immunity against intra-cellular infections. This review focuses on the current achievements in genomic studies devoted to the identification of genes important for the implementation of the immune response and protection against the development of the infection in different populations in the world.

Background: The majority of miscarriages are sporadic; however, 1-5% of couples experience recurrent pregnancy loss (RPL). Approximately 50-60% of miscarriages result from chromosomal abnormalities. Currently, there are conflicting reports regarding the rates of chromosomal abnormalities between recurrent and sporadic pregnancy losses.

Methods: A retrospective comparative cytogenetic analysis of 442 RPL and 466 sporadic abortions (SA) was performed. Maternal age and medical background were evaluated, and chromosomal abnormality rates were compared between groups.

Results: The frequency of embryos with abnormal karyotypes was significantly higher in SA compared to RPL (56.7 and 46.6%, respectively), and abortions from women under 30 years of age were the main contributor to this difference. An age-dependent increase in the abnormal karyotype rate was observed in two groups of women - those with SA [53.0 and 70.1% for younger and older (≥35-year-old) mothers, respectively] and those with idiopathic RPL without any concomitant reproductive pathology (46.5 and 78.4% for younger and older mothers) - but not in the group of women with RPL associated with concomitant reproductive pathology. The incidence of recurrent abnormal karyotypes in subsequent miscarriages was significantly higher than random probability (odds ratio = 22.75).

Conclusion: Our findings highlight the variability in the risk of aneuploidy in recurrent abortion.

The widespread application of array comparative genomic hybridization (aCGH) has provided new insights into the clinical significance of copy number variations (CNVs) in the human genome. Many microdeletion syndromes have recently been linked to corresponding reciprocal microduplication syndromes related to CNVs in the same chromosomal regions. However, the extent of CNVs may not be restricted to only microduplications but may also include microtriplications or even quadruplications. 4q21 microdeletion syndrome is one of these recently described syndromes. The phenotype includes growth restriction, neonatal hypotonia, severe developmental delay, absent or delayed speech, and distinct facial features. The minimal critical deleted region, which is 1.3 Mb in size, contains the PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1 genes. Here, we report a 5.4-year-old girl with developmental delay, absence of speech, muscular hypertension, macrocephaly, a broad forehead, frontal bossing, relatively elongated extremities, a vascular malignant hemangioma in anamnesis, and elongated sigmoid colon. aCGH revealed a microtriplication at 4q21.21-q21.22 that was 1.61 Mb in size. This de novo microtriplication included nine genes (BMP3, PRKG2, RASGEF1B, HNRNPD, HNRPDL, ENOPH1, TMEM150C, LINC00575, and SCD5) and overlapped with the minimal critical region for 4q21 microdeletion syndrome. Some clinical features of the patient were similar to those of 4q21 microdeletion (macrocephaly, frontal bossing, developmental delay, absence of speech, and anxiety), whereas others were mirrored (elongated extremities and muscular hypertension). The first identified case of a de novo microtriplication at 4q21.21-q21.22 emphasizes the clinical significance of CNVs at 4q21 for patients with developmental delay and absence of speech

Objectives: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Methods: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared.

Results: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant.

Conclusions: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia