Мукополисахаридоз-плюс синдром (МПСПС, OMIM # 617303) представляет собой редкое аутосомно-рецессивное наследственное заболевание, вызванное патогенным вариантом c.1492C>T в экзоне 12 гена VPS33A. Заболевание характеризуется фенотипом «гаргоилизма», включающим скелетные аномалии, поражение сердца, контрактуры суставов, задержку психомоторного и физического развития, а также дополнительные нарушения со стороны почек и гемопоэтической системы. Впервые клиническая картина МПСПС была описана в 2014 году врачами медико-генетического центра г. Якутска, а молекулярно-генетическая причина была установлена в 2017 году. В работе при анализе неравновесия по сцеплению 11 микросателлитных маркёров установлен «гаплотип основателя» локуса МПСПС, что, вероятно, свидетельствует о накоплении мутации в результате эффекта основателя. Определено время распространения мутации в Якутии, которое составило 2312 ± 1375 лет. Среднее значение числа поколений, прошедших после начала распространения патогенного варианта c.1492C> T в якутской популяции, составило 92,5.

Ишемическая болезнь сердца представляет собой важную медико-социальную проблему. Наиболее тяжелой формой заболевания, с поражением всех слоев сердечной мышцы, считается инфаркт миокарда с подъемом сегмента ST (ИМпST). Одним из диагностических критериев дисфункции эндотелия при инфаркте миокарда является уровень sE-селектина – молекулы клеточной адгезии, осуществляющей рекрутинг нейтрофилов и индукцию нейтрофильного воспаления. В настоящем исследовании изучен интронный полиморфизм (rs5353, rs3917412, rs1534904) гена SELE, кодирующего Е-селектин, у пациентов с ИМпST. Проанализированы две выборки: пациенты с ИМпST (n = 74) и популяционная выборка г. Томска (n = 136). По частотам генотипов rs5353 в гене SELE зарегистрированы статистически значимые различия между пациентами и контрольной выборкой (p = 0.004). Генотип СС является рисковым по отношению к ИМпST (OR = 6.93, CI:95 % (1.84–26.04), χ2 = 8.69, p = 0.002). Проанализированные маркеры не изучались ранее при сердечно-сосудистых заболеваниях и вообще редко привлекались к ассоциативным исследованиям; в ведущих базах данных отсутствует информация об ассоциациях этих маркеров с заболеваниями. Вместе с тем все три варианта по классификации RegulomeDB относятся к функциональному классу 1f и, соответственно, с высокой вероятностью обладают регуляторным потенциалом относительно не только гена SELE, но и других генов близлежащего региона. Анализ функциональной значимости изученных маркеров показал наличие более обширного, чем один ген, региона, корегулируемого данными нуклеотидными заменами. Выявленная в настоящем исследовании ассоциация rs5353 с ИМпST еще раз подтверждает вовлеченность гена SELE в развитие сердечно-сосудистых заболеваний. Не исключено, что опосредованно (через системы воспаления, иммунного ответа и репарации ДНК) весь этот регион генома может быть вовлечен в патогенез сердечно-сосудистых заболеваний.

Background: Mitochondrial dysfunction in myocardium cells has been implicated in arrhythmogenesis, including ventricular tachycardia (VT). A carriage of point mitochondrial DNA (mtDNA) polymorphisms may contribute to the risk of certain arrhythmias. Therefore, it is hypothesized that mtDNA genotype could predict the risk of sustained VT (SVT). We aimed to explore whether specific mtDNA polymorphisms of peripheral blood mononuclear cells (PBMC) can serve as biomarkers for predicting the risk of SVT in patients with indications for an implantable cardioverter-defibrillator (ICD). Methods: A total of 122 patients with ICD implantation indications who underwent transthoracic echocardiography (TTE) were enrolled in the study. Total DNA from PBMC was isolated using the phenolchloroform extraction method. Genotyping of mtDNA polymorphisms A2706G, G3010A and G9055A was performed using restriction fragment length polymorphism analysis. Correlations between clinical parameters and mtDNA polymorphisms with SVT registered prior to ICD implantation were evaluated. Based on our data, we developed a risk model for SVT. Results: Prior to ICD implantation, 70 (56.6%) patients had SVT (1st group) and 52 (43.4%) patients did not have SVT (2nd group). Patients with SVT were significantly older than patients without SVT (66.9 ± 9.9 year vs. 59.5 ± 10.6 year, p < 0.001), had a lower value estimated glomerular filtration rate (eGFR) (65.7 ± 19.7 mL/min/1.73 m2 vs. 77.9 ± 16.1 mL/min/1.73 m2, p < 0.001) and less frequently had A2706G mtDNA polymorphism (55.7% vs. 76.9%, p = 0.015). According to the multivariable logistic regression, age (odds ratio (OR) = 1.055, 95% confidence interval (CI) 1.009–1.103, p = 0.017), eGFR (OR = 0.974, 95% CI 0.949–0.999, p = 0.041) and absence of A2706G mtDNA polymorphism (OR = 0.335, 95% CI 0.141–0.797, p = 0.013) were independently associated with the SVT. We constructed a logistic equation with calculation of the cut-off value. The discriminative ability of the receiver operating characteristic curve (area under the curve) was 0.761 (95% confidence interval 0.675–0.833; sensitivity 65.71%; specificity 76.92%). Conclusions: In patients with ICD implantation indications, a carriage of mtDNA polymorphism A2706G is associated with SVT. Our risk model including age, eGFR and absence of A2706G mtDNA substitution was able to distinguish patients with SVT. Further investigations of their predictive significance are warranted. 

 Преждевременное половое созревание (ППС, Е30.1, Е22.8, Е30.9 по МКБ 10, MIM 176400, 615346) у детей – заболевание, при котором вторичные половые признаки появляются раньше возрастной нормы. Сроки полового созревания регулируются сложным взаимодействием генетических и эпигенетических факторов, а также факторов окружающей среды и питания. Цель настоящего исследования – поиск генетических причин формирования у девочек клинической картины ППС. Поиск клинически значимых генетических вариантов (патогенных, вероятно патогенных вариантов или вариантов с неопределенным клиническим значением (variant of uncertain significance, VUS)) проведен в генах KISS1, KISS1R (GPR54), DLK1 и MKRN3 у девочек с клинической картиной ППС и нормальным кариотипом методом таргетного массового параллельного секвенирования. Все найденные генетические варианты были подтверждены методом секвенирования ДНК по Сэнгеру. Патогенность идентифицированных генетических вариантов и функциональная значимость кодируемого ими белка проанализированы с использованием онлайн-алгоритмов прогнозирования патогенности Variant Effect Predictor, Franklin и Varsome, а также PolyPhen2 (согласно рекомендациям по интерпретации результатов анализа NGS). Клинически значимые генетические варианты были обнаружены в гетерозиготном состоянии в генах KISS1R, DLK1 и MKRN3 у 5 из 52 пробандов (9.6 %) с ППС, из них 3 из 33 (9.1 %) – в группе с центральным ППС и 2 из 19 (10.5 %) – в группе с гонадотропин-независимой формой ППС. Два ребенка с гонадотропин-независимой формой ППС имели VUS в гене KISS1R (c.191T>C, p.Ile64Thr и c.233A>G, p.Asn78Ser), один из которых был унаследован от отца, второй – от матери. У остальных пациентов с центральным ППС были вероятно патогенные генетические варианты DLK1:c.373delC(p.Gln125fs) de novo и DLK1:c.480delT(p.Gly161Alafs*49) отцовского происхождения. Еще один пробанд имел вариант VUS в гене MKRN3 (c.1487A>G, p.His496Arg), унаследованный от отца. Все выявленные генетические варианты описаны впервые при ППС. Таким образом, в настоящем исследовании найдены новые генетические варианты в генах KISS1R, DLK1 и MKRN3 у девочек с преждевременным половым созреванием.

The goal of this study was to analyze copy number variations (CNVs) in spontaneous abortions with a euploid karyotype, irrespective of the method used for CNV detection. This systematic review was performed in accordance with the PRISMA guidelines. Articles published between 2006 and 2023 were selected through the PubMed database. Studies were included if they involved CNV analysis in spontaneous abortions using any CNV detection method. The pathogenic significance of CNVs was interpreted based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Nineteen publications met the inclusion criteria. A total of 1425 CNVs were identified in 550 samples from 3953 euploid spontaneous abortions, representing 14% of the cases. Among the detected CNVs, 9% were classified as pathogenic, and 7.5% were likely pathogenic. The most frequently observed pathogenic CNVs included 22q11.2 deletion/duplication, 16p13.11 deletion, 15q11.2 deletion/duplication, 1p36.33 duplication, and 17p13.3 duplication. The genomic regions with the highest frequency of CNVs, regardless of their pathogenic effect, were 8q24.3, 16p13.3, 21q22.3, Xp22.33, Xp22.31, and Xq28. No clear associations were found between specific CNVs and pregnancy loss. However, deletions in the 22q11.2 region emerged as the most likely candidates contributing to lethality during the early stages of embryonic development.

Ischemic heart disease (IHD) is an important medical and social problem. ST-elevation myocardial infarction (STEMI) is the most severe form of IHD, affecting all layers of the heart muscle. One of the diagnostic criteria for endothe lial dysfunction in myocardial infarction is the level of sE selectin, a cell adhesion molecule that recruits neutrophils and induces neutrophil inflammation. The aim of this study is to investigate intronic polymorphisms rs5353, rs3917412 and rs1534904 of the E-selectin coding gene SELE in patients with STEMI. We have analyzed a group of patients with STEMI (n = 74) and a population sample of Tomsk (n = 136) as the control group. The frequencies of the rs5353 genotypes in the SELE gene have shown statistically significant differences between patients and the control sample (p = 0.004). The CC genotype is a predisposing factor to STEMI (OR = 6.93, CI:95 % (1.84–26.04), χ2 = 8.69, p = 0.002). The analyzed markers were not studied previously in cardiovascular diseases (CVDs) and were rarely involved in association studies at all; there is no information on these SNPs in the leading databases. At the same time, all three variants, according to the RegulomeDB classification, belong to the functional class 1f, and are highly likely to have regulatory potential rela tive not only to the SELE gene, but also to other genes in the nearby region. The analysis of the functional significance of the studied markers has shown the presence of a region more extensive than one gene, which is co-regulated by the studied nucleotide substitutions. The association of rs5353 with STEMI identified in this study once again confirms the involvement of the SELE gene in the pathogenesis of CVDs. It is possible that this entire region of the genome may be involved indirectly in the pathogenesis of CVD through the systems of inflammation, immune response and DNA repair.

Aortic aneurysm (AA) and atherosclerosis (AS) of various vascular beds are asymptomatic for a long time and are relatively common pathological conditions that lead to life-threatening and disabling complications. In this review, we discuss the current understanding of the high variation in direct and inverse comorbidity of AA and AS as presented in scientific publications. Estimates of AA and AS comorbidity depend on several factors, such as the location of AA (ascending or descending thoracic aorta or abdominal aorta), familial or sporadic cases of AA, syndromic forms of AA, and/or aortic valve pathology (bicuspid aortic valve [BAV]). To identify the causes of the comorbidity of AA and AS, it is important to consider and characterise many factors in detail. These factors include clinical characteristics of the patients included in a study (age, sex) and risk factors (mainly the presence of monogenic forms and BAV, hypertension, hypercholesterolaemia, diabetes mellitus, and cigarette smoking). Additionally, it is essential to consider characteristics of the disease course and the nature of multimorbidity and to take into account pathologies not only of the cardiovascular system but also of other organ systems, with special attention to metabolic and endocrine disorders.

Background: The X chromosome is enriched with genes related to brain development, and the hemizygous state of these genes in men causes some difficulties in the clinical interpretation of copy number variations (CNVs). In this study, we present data on the frequency and spectrum of CNVs on the X chromosome in a cohort of patients with neurodevelopmental disorders (NDDs).
Methods: Chromosomal microarray analysis was performed for 1175 patients with NDDs. CNVs were confirmed by real-time quantitative PCR. X chromosome inactivation was analysed by methyl-sensitive PCR. To determine the pathogenic significance of the CNVs, several criteria, including the origin (inherited or de novo), variant type (microdeletion or microduplication), and X chromosome inactivation pattern in asymptomatic and symptomatic carriers, were considered. Additionally, the spectrum, size and molecular bases of copy number changes in genes or gene regions involved in the development of the pathological phenotype in each patient were considered.
Results: CNVs on the X chromosome were identified in 33 patients (2.8%). Duplications and triplications (27 cases) were four times more common than deletions (6 cases). In 74% of patients, CNVs were of maternal origin; in 10% they were of paternal origin; and in 16% they arose de novo. The frequency of skewed X inactivation among family members who were healthy carriers of pathogenic and likely pathogenic CNVs and variants of uncertain significance (VUSs) on the X chromosome was 23%. For the first time, we reported several CNVs, including a pathogenic microdeletion at Xq26.1q26.2 involving the ARHGAP36 gene and a microduplication at Xp22.2 involving the OFD1 gene, CONCLUSIONS: This study expands on the frequency and spectrum of CNVs in patients with NDDs. Pathogenic variants on the X chromosome were present in 15% of cases, LP in 12%, VUS in 57%, and LB in 16% of cases. Previously unreported CNVs aid in the identification of new structural variants and genes associated with X-linked intellectual disability. We propose to consider the X-chromosome inactivation status when assessing the pathogenetic significance of CNVs using the ACMG algorithm (American College of Medical Genetics).

We report a novel variant in the MACF1 gene that caused a congenital brain anomaly (lissencephaly, brainstem hypoplasia, and agenesis of the corpus callosum) in a patient with severe neurodevelopmental delay and drug-resistant epilepsy. The patient was nonresponsive, nonverbal, and nonambulatory and experienced daily generalized myoclonic seizures, generalized muscle weakness, dysphagia, and faecal and urinary incontinence. Whole-exome sequencing revealed a missense heterozygous MACF1 variant, c.21878A>G (p.Asp7293Gly). The de novo origin of the variant was confrmed by trio Sanger sequencing. The variant was not reported previously in the gnomAD, ExAC, and 1000 Genomes databases. Our report expands the genetic heterogeneity of a rare type of lissencephaly.

Copy number variations of the human CNTN6 gene, resulting from megabase-scale microdeletions or microduplications in the 3p26.3 region, are frequently implicated in neurodevelopmental disorders such as intellectual disability and developmental delay. However, duplication of the full-length human CNTN6 gene presents with variable penetrance, resulting in phenotypes that range from neurodevelopmental disorders to no visible pathologies, even within the same family. Previously, we obtained a set of induced pluripotent stem cell lines derived from a patient with a CNTN6 gene duplication and from two healthy donors. Our findings demonstrated that CNTN6 expression in neurons carrying the duplication was significantly reduced. Additionally, the expression from the CNTN6 duplicated allele was markedly lower compared to the wild-type allele. Here, we first introduce a system for correcting megabase-scale duplications in induced pluripotent stem cells and secondly analyze the impact of this correction on CNTN6 gene expression. We showed that the deletion of one copy of the CNTN6 duplication did not affect the expression levels of the remaining allele in the neuronal cells.

Background: Chromosome 3q29 duplication syndrome is a rare chromosomal disorder with a frequency of 1:5000 in patients with a neurodevelopmental phenotype. The syndrome is characterized by phenotypic polymorphism and reduced penetrance. Methods: Patients were investigated by performing a cytogenetic analysis of GTG-banded metaphases, aCGH with the SurePrint G3 Human CGH Microarray 8×60K, qPCR, FISH, and WES. Results: Here, we report five new patients with atypical duplications overlapping with the 3q29 duplication syndrome region and no other genetic findings. In two patients, duplications were found in the single BDH1 gene, a candidate gene for the 3q29 duplication phenotype. For the first time, we delineated and described the smallest minimal critical region, including the single BDH1 gene; in our patients, this region was associated with ASD, heart defects, biliary tract dysfunction, and obesity. The frequencies of the pathological phenotypes in duplication carriers reported in the literature were calculated and compared with those in patients with 3q29 deletions. Most of the phenotypes were observed in both groups but were significantly less common among individuals with 3q29 duplications. Mirrored phenotypes in patients with duplications and deletions included overweight and weight deficit. Schizophrenia, generalized anxiety disorder, and recurrent ear infections were unique phenotypes of patients carrying deletions. Conclusion: Chromosome 3q29 duplication syndrome is characterized by a complex genetic architecture and clinical polymorphism.

Objective: To evaluate the frequency and severity of various clinical symptoms of Parkinson's disease (PD) depending on the BDNF rs6265 polymorphism.

Material and methods: The study included 533 patients with PD. The stage of PD was assessed using the Hoehn and Yahr scale (1967), motor symptoms were evaluated with MDS-UPDRS. Assessment of non-motor symptoms (NMS) in PD was conducted using the Beck Depression Inventory II (BDI-II); the Hospital Anxiety and Depression Scale (HADS); the Apathy Scale; the Montreal Cognitive Assessment (MoCA test); the Questionnaire for Impulsive-Compulsive Disorders in PD -Rating Scale (QUIP-RS). Genotyping of the BDNF variant (rs6265) was performed using real-time PCR with TaqMan probes.

Results: Most PD patients have a combination of NMS increasing as the disease progresses and is determined by molecular-genetic individual characteristics. There are significant differences in the severity of motor symptoms and NMS: individuals with the AA genotype showed significantly pronounced motor symptoms (p<0.0001); emotional-affective symptoms (p<0.0001); cognitive and impulsive behavioral disorders (p<0.0001).

Conclusion: The rs6265 BDNF allele A is associated with a wide range of NMS, increasing the risk of their development in patients with PD, thus playing the important role in the etiopathogenesis of this pathology.

Chromosomal aberrations, such as whole-chromosome aneuploidies (WCA), segmental aneuploidies (SA), whole-chromosome mosaicism (WCM), and segmental mosaicism (SM), are key factors influencing embryonic development and the outcomes of fertility programs. This analytic review critically examines the prevalence and origins of these genetic abnormalities, emphasizing the significant maternal contribution to WCA and the age-related nature of these aberrations. In contrast, SA, WCM, and SM appear largely age-independent and show considerable variability across studies, mainly due to technical artifacts and methodological differences. By analyzing the accumulated data, scrutinizing methodological discrepancies in preimplantation genetic testing for aneuploidies (PGT-A), and distinguishing between biological phenomena and artifacts, this review aims to clarify the current understanding of chromosomal aberrations in human embryos and their impact on reproductive health.

Whole exome sequencing of peripheral blood samples from Tuvan females diagnosed with breast and ovarian cancers (BC/OC) was performed to search for new genes involved in BC/OC pathogenesis. Considering the high cost of whole exome sequencing and study material requirements, 9 samples were selected from 61 genomic DNA samples. A mutation in the LGR4 gene (rs34804482) involved in the tumor-mediated Wnt signaling pathway and a mutation in the BRWD1 gene (rs147211854) involved in chromatin remodeling were identifed in BC patients. A mutation in the CITED2 gene (rs77963348) involved in the pathogenesis of primary ovarian insufciency was identifed in a patient with OC and a history of infertility. A mutation in the PDGFRA gene (rs2291591) was identifed in two BC/OC patients. LRG4, BRWD1, PDGFRA, and CITED2 germline pathogenic mutations were discovered in Tuvan women diagnosed with BC/OC for the frst time.

Our understanding of human genes – particularly their structure, functions, and regulatory mechanisms – is still limited. The biological role of approximately 20 % of human proteins has not been established yet, and the molecular functions of the known part of the proteome remain poorly understood. This hinders progress in basic and applied biological and medical sciences, especially in treating hereditary diseases, which are caused by mutations and polymorphic variants in individual genes. Therefore, it is crucial to comprehend the mechanisms of protein functioning to address this problem. This further emphasizes the importance of investigating gene functions and molecular pathogenetic pathways associated with single-gene inherited diseases. This review focuses on the TCF4 gene that encodes a transcription factor crucial for nervous system development and functioning. Pathogenic variants in this gene have been linked to a rare genetic disorder, Pitt–Hopkins syndrome, and TCF4 polymorphic variants are associated with several socially significant diseases, including various psychiatric disorders. The pathogenetic mechanisms of these conditions remain unexplored, and the knowledge about TCF4 upregulation and its target genes is limited. TCF4 can be expressed in various isoforms due to the complex structure and regulation of its gene, which complicates the investigation of the protein’s functions. Here, we consider the structure and functions of the TCF4 transcription factor. We discuss its potential target genes and the possible loss-of-function pathogenetic mechanisms identified in animal and cellular models of Pitt–Hopkins syndrome. The review also examines the advantages and limitations of potential therapies for Pitt–Hopkins syndrome that are based on TCF4 dosage compensation or altering the activity of TCF4 target genes.