PACS1 neurodevelopmental disorder (Schuurs-Hoeijmakers syndrome; MIM #615009) is a rare autosomal dominant genetic syndrome characterized by developmental delay, intellectual disability, dysmorphic features, and rare seizures. The article describes a clinical case of PACS1 syndrome in a female patient with developmental delay, speech disorder, motor development delay and epilepsy coupled to described variants in PACS1 gene (rs398123009, chr11:6621120, c.607C>T, p.Arg203Trp). Knowing PACS1 syndrome molecular mechanisms is important not only for genotype-phenotypic correlation, but also for developing new therapeutic approaches that could improve the quality of patients’ life.

Background. Prion diseases or transmissible spongiform encephalopathies are a group of neurodegenerative disorders characterized by rapidly progressive dementia and movement disorders. Prion diseases can be acquired, sporadic, genetic (inherited), and are characterized by the accumulation and aggregation of prions or abnormally coiled proteins. The diseases have a long incubation period (years) but progress rapidly after the manifestation of clinical symptoms. The most common human prion diseases are sporadic in nature. Prion diseases include sporadic Creutzfeldt – Jakob disease, as well as rare cases of sporadic fatal insomnia and variable protease-sensitive prionopathy. The diseases have a long incubation period (years), but progress rapidly after the manifestation of clinical symptoms. Fatal familial insomnia (Insomnia, fatal familial; OMIM: # 600072) is a rare autosomal dominant neurodegenerative disease with high penetrance and associated with mutation in PRNP gene.Results. The article presents clinical case of 15-year-old patient with severe mental development disorder, motor excitability, hyperactivity of sympathetic nervous system and insomnia. The previously described variant in PRNP gene (D178N) was detected by whole exome sequencing. Validation of the mutation in the proband and segregation analysis were carried out: mutation c.532G>A, Asp178Asn in PRNP gene was identified in the proband and his 50-year-old father, who had no signs of prion disease. at the time of the study. Additionally, adenine in the 358th position was found in a homozygous state, which is responsible for the frequent M129M polymorphism in Sanger sequencing of PRNP gene in the proband and his father.Conclusion. The description of the clinical case of fatal familial insomnia in Russia presented by the authors clearly shows the likely difficulties that doctors may face when examining such patients. The diagnosis (clinical, genetic using massively parallel sequencing methods) remains important in relation to medical genetic counseling and family planning, since methods of pathogenetic therapy for hereditary prion diseases have not currently been developed.

In most cases, variants of nucleotide sequence in the SEMA6B gene account for developing the phenotype of progressive myoclonus epilepsy and, to a lesser extent, developmental encephalopathy with or without epilepsy. Loss-of-function variants in nucleotide sequence localized mainly in exon 17 of the SEMA6B gene contribute to production of aberrant proteins with “toxic” functions. A clinical case of status epilepsy in a patient with a variant in the SEMA6B gene (c.2506delС; p.His836ThrfsTer136; NM_032108.4) is described in the article that expands our knowledge regarding the SEMA6B gene variants resulting in progressive myoclonus epilepsy.

Introduction. Developmental and epileptic encephalopathy are severe developmental disorders of the nervous system, characterized by recurrent epileptic seizures that begin over the neonatal period or childhood, accompanied by psychomotor retardation and intellectual disability. Massively parallel sequencing is a technology used to determine the complete nucleotide sequence of DNA or RNA. The technology is characterized by the high productivity and speed, marking the beginning of the golden age of genetics, allowing large volumes of DNA to be sequenced quickly and efficiently at lower costs. The aim of this study is to evaluate the effectiveness of whole- exome sequencing as a first-line genetic test in patients with developmental and epileptic encephalopathy and detect the structure of identified variants in the Russian population. Materials and methods. Patients with drug-resistant seizures, onset in neonatal and early childhood, hospitalized in the Psychoneurological Department during 2017–2023. All patients underwent clinical and genealogical analysis, video-EEG and MRI of the brain, and whole-exome sequencing. Results. The main result obtained in the study analysis of patients who underwent whole exome sequencing for the period of 2017-2023 was the detection rate of variants in genes associated with developmental and epileptic encephalopathy (21.7%; 71/331). Of these, 35/71 (49.3%) had pathogenic and probably pathogenic variants of the nucleotide sequence. Based on the results of whole exome sequencing patients were selected for the most effective targeted antiepileptic drugs. Conclusion. The use of whole-exome sequencing as a first-line molecular genetic test in patients with developmental and epileptic encephalopathy has been shown to be highly effective. Making an accurate genetic diagnosis is a fundamental background for precision therapy. Personalized medicine, that is, the attempt to personalize prevention, diagnosis, and treatment as much as possible according to the characteristics and needs of the patient, should be the main goal of clinical research and a new direction of modern medicine.

Введение. Прионные заболевания, или трансмиссивные губкообразные энцефалопатии, – группа нейродегенеративных расстройств, характеризующихся быстро прогрессирующими деменцией и двигательными нарушениями. Прионные заболевания могут быть приобретенными, спорадическими, генетическими (наследоваться) и характеризуются накоплением и агрегацией прионов или аномально свернутых белков. Заболевания имеют длительный инкубационный период (годы), но быстро прогрессируют после манифестации клинических симптомов. Наиболее распространенные прионные заболевания человека носят спорадический характер. К прионным заболеваниям относятся спорадическая болезнь Крейтцфельдта – Якоба, а также редкие проявления спорадической бессонницы со смертельным исходом и вариабельная протеаз-чувствительная прионопатия. Фатальная семейная бессонница (Insomnia fatal familial; OMIM: # 600072) – редкое аутосомно-доминантное нейродегенеративное заболевание с высокой пенетрантностью, развивается вследствие миссенс-мутации в кодоне 178 (D178N) гена PRNP, локализованном на хромосоме 20. Результаты. В статье представлен клинический случай пациента 15 лет с выраженными нарушениями психического развития, двигательным возбуждением, гиперактивностью симпатической нервной системы и бессонницей. При проведении полноэкзомного секвенирования выявлен ранее описанный вариант в гене PRNP (D178N). Проведена валидация мутации у пробанда и сегрегационный анализ: мутация c.532G>A, Asp178Asn в гене PRNP выявлена у пробанда и его 50-летнего отца, у которого на момент исследования не было отмечено признаков прионного заболевания. Дополнительно при проведении секвенирования по Сэнгеру гена PRNP у пробанда и его отца был обнаружен в 358-м положении аденин в гомозиготном состоянии, отвечающий за частый полиморфизм М129М. Заключение. Представленное авторами описание клинического случая фатальной семейной бессонницы в России наглядно показывает вероятные сложности, с которыми могут столкнуться врачи при обследовании таких пациентов. Своевременная диагностика (клиническая, генетическая с использованием методов массового параллельного секвенирования) остается важной в отношении медико-генетического консультирования и планирования семьи, так как методов патогенетической терапии наследственных прионных заболеваний в настоящее время не разработано. Background. Prion diseases or transmissible spongiform encephalopathies are a group of neurodegenerative disorders characterized by rapidly progressive dementia and movement disorders. Prion diseases can be acquired, sporadic, genetic (inherited), and are characterized by the accumulation and aggregation of prions or abnormally coiled proteins. The diseases have a long incubation period (years) but progress rapidly after the manifestation of clinical symptoms. The most common human prion diseases are sporadic in nature. Prion diseases include sporadic Creutzfeldt – Jakob disease, as well as rare cases of sporadic fatal insomnia and variable protease-sensitive prionopathy. The diseases have a long incubation period (years), but progress rapidly after the manifestation of clinical symptoms. Fatal familial insomnia (Insomnia, fatal familial; OMIM: # 600072) is a rare autosomal dominant neurodegenerative disease with high penetrance and associated with mutation in PRNP gene. Results. The article presents clinical case of 15-year-old patient with severe mental development disorder, motor excitability, hyperactivity of sympathetic nervous system and insomnia. The previously described variant in PRNP gene (D178N) was detected by whole exome sequencing. Validation of the mutation in the proband and segregation analysis were carried out: mutation c.532G>A, Asp178Asn in PRNP gene was identified in the proband and his 50-year-old father, who had no signs of prion disease. at the time of the study. Additionally, adenine in the 358th position was found in a homozygous state, which is responsible for the frequent M129M polymorphism in Sanger sequencing of PRNP gene in the proband and his father. Conclusion. The description of the clinical case of fatal familial insomnia in Russia presented by the authors clearly shows the likely difficulties that doctors may face when examining such patients. The diagnosis (clinical, genetic using massively parallel sequencing methods) remains important in relation to medical genetic counseling and family planning, since methods of pathogenetic therapy for hereditary prion diseases have not currently been developed.

Focal epilepsy is the most common type of epilepsy accounting for 60–70% of all cases of this pathology. We present two familial cases of focal epilepsy associated with a nucleotide sequence variant in DEPDC5 gene. Clinical and ancestry examination was performed by using instrumental (magnetic resonance imaging, video-electroencephalography) and genetic testing methods. The nucleotide sequence variants in DEPDC5 gene were found in two probands and paired fathers with epilepsy. Focal cortical dysplasia was detected only in the father of Proband 1 as well as Proband 2 with resistant epilepsy and severe cognitive deficit. Hence, such clinical cases confirm that pathogenic variants in DEPDC5 gene are related with familial focal epilepsy, which clinical manifestation may depend on the type of identified mutation. The study of genotype-phenotype correlations is necessary to apply proper therapy. Before surgical treatment of epilepsy, the genetic testing by whole exome or whole genome sequencing should be performed.

The article presents the clinical cases of 6 patients with epilepsy, psychomotor and speech developmental delay. The heterozygous variants of the nucleotide sequence in SPTAN1 gene were detected by whole exome sequencing. Mutations in SPTAN1 gene have been described in patients with developmental and epileptic encephalopathy 5 (ОMIM: 613477). The clinical history, electroencephalographic and magnetic resonance imaging data of our patients are similar in children with variants in SPTAN1 gene described previously. It was shown that variants in SPTAN1 gene located closer to the C-terminal region are associated with a more severe phenotype, whereas the variants near the N-region – with a milder course of the disease without structural brain anomalies. However, further research is necessary in the future to better understand genotype-phenotypic correlations in SPTAN1-associated encephalopathy.

The contribution of genetic factors to development of neurological diseases has long been recognized, and the majority of the advances coupled to using molecular genetic technologies resulted in identifying genes associated with the pathology of developing nervous system. The review is aimed at demonstrating opportunities and achievements of using massive parallel sequencing technology in the diagnosis of a disease with damage to nervous system. Currently, next-generation sequencing (NGS) technology in the genetic diagnosis of epilepsy relies on targeted gene panels, whole exome sequencing or whole genome sequencing. Integrating genetic and genomic analysis into clinical practice to establish clear molecular diagnoses for previously undiagnosed patients will avoid further unnecessary diagnosis and therefore lead to greater healthcare cost savings over time. The use of biomarkers will contribute to the prediction of disease outcome and therapy decision-making.

The hepatitis delta virus (HDV) is believed to be a vanishing infection in countries with successful hepatitis B virus (HBV) vaccination programs. We assessed the current status of HDV infection in Tuva, a region of the Russia that has been highly endemic for HBV. The proportion of HDV-infected patients among HBsAg-positive patients in the regional registry in 2020 was 32.7% (786/2401). An analysis of the medical records of 514 HDV patients demonstrated that 37.5% (193/514) had liver cirrhosis at the first doctor's visit, and 7.4% of patients lived in families where another family member had HDV. All HDV patients were infected with genotype HDV-1, 94.5% had HBV genotype D, and 5.5% had genotype A. A serosurvey conducted among 1170 healthy volunteers showed that the average detection rate of HBsAg with anti-HDV was 1.0% (95% CI: 0.57-1.81%). No anti-HDV positive samples were detected in participants aged under 30 years. The HBsAg/anti-HDV positivity rate peaked at 7.4% in patients aged 50-59 years, which was significantly higher than in a similar age cohort surveyed in 2008 (1.6%, p < .0001). A Bayesian analysis showed that HDV circulation in Tuva resulted from two waves of introduction, the first in the 1810s (95% HPD: 1741-1834) from Central Asia, and the second in the 1960s (95% HPD: 1953-1979) from Russia. HBV has a much longer history of circulation in Tuva with the MRCA for the predominant genotype HBV-D dated to 972 (95% HPD: 535-1253) for subtype D1, 1274 (95% HPD: 936-1384) for D2, and 1173 (95% HPD: 1005-1618) for D3. A SkyGrid reconstruction of population dynamics showed an increase in the intensity of HDV spread in recent decades. This situation shows the need for HDV screening and prevention measures among people living with HBV.

The article provides information about the nature of atherogenic disorders in children. Much attention is devoted to the problem of the pathogenesis of atherosclerosis, the substantiation of its stress theory, whereas nosological essence is rejected. Atherosclerosis is considered as an evolutionary, genetically determined pathophysiological process that accompanies a person from conception to death, affecting the health quality and life expectancy. Attention is drawn to the issues of susceptibility to atherogenic disorders in children, which explanation allows us to solve the problems of their prevention and prophylaxis.

Focal epilepsy is the most common type of epilepsy accounting for 60–70% of all cases of this pathology. We present two familial cases of focal epilepsy associated with a nucleotide sequence variant in DEPDC5 gene. Clinical and ancestry examination was performed by using instrumental (magnetic resonance imaging, video-electroencephalography) and genetic testing methods. The nucleotide sequence variants in DEPDC5 gene were found in two probands and paired fathers with epilepsy. Focal cortical dysplasia was detected only in the father of Proband 1 as well as Proband 2 with resistant epilepsy and severe cognitive deficit. Hence, such clinical cases confirm that pathogenic variants in DEPDC5 gene are related with familial focal epilepsy, which clinical manifestation may depend on the type of identified mutation. The study of genotype-phenotype correlations is necessary to apply proper therapy. Before surgical treatment of epilepsy, the genetic testing by whole exome or whole genome sequencing should be performed.

The clinical case of a patient with congenital contractures of the lower and upper limbs, face, seizures, facial dysmorphias, motor disorders and psychomotor development delay is presented. The proband with Freeman–Sheldon syndrome had no mutations in genes associated with distal arthrogryposis. Chromosomal microarray analysis revealed terminal duplication of the long arm of chromosome 9 and terminal microdeletions of the short arm of chromosome 20 – 46,XX.arr[hg38]9q33.3q34.3 (127016168_138124666) x3,20p13 (259113_1003183)x1 in the de novo status. This clinical observation demonstrates an opportunity of using innovative molecular cytogenetic technologies in the search for disease-related genetic causes in the absence of mutations detected by whole exome sequencing.

The data on hepatitis A virus (HAV) seroprevalence are critical for the implementation of a universal mass vaccination (UMV) strategy. The latter has not been implemented in Russia; however, regional child vaccination programs have been adopted in some parts of the country. The aim of this study is to assess changes in HAV immunity within the last decade in regions of Russia with different vaccination strategies and different vaccination coverage rates. In regions where UMV has not been implemented and HAV vaccination coverage rates do not exceed the national average, the 50% seroprevalence threshold has shifted in the Moscow region from people aged under 40 years in 2008 to people aged over 59 years in 2020, and from people aged under 30 years to people aged over 40 years in the Khabarovsk region. In two regions (Yakutia and Sverdlovsk), a two-dose-based UMV scheme has been in place since 2011 and 2003, respectively, and in Tuva single-dose child immunization was launched in 2012. These regional programs have resulted in a significant increase in HAV seroprevalence in children and adolescents. In Yakutia, 50% herd immunity had been achieved by 2020 in age groups under 20 years, compared to 20–30% seroprevalence rates in 2008. In the Sverdlovsk region, HAV immunity has increased to >65% over the decade in children aged over 10 years, adolescents and young adults, whereas it declined in older age groups. However, a three-fold drop in HAV immunity has occurred in children under 10 years of age, reflecting a significant decline in vaccination coverage. In Tuva, HAV immunity rates in children under 10 years old increased two-fold to exceed 50% by 2020. These data suggest that UMV should be implemented on a national level. Measures to control vaccination coverage and catch-up vaccination campaigns are recommended in order to maintain the effectiveness of existing HAV vaccination programs.

В последние десятилетия достижения в области применения полноэкзомных и полногеномных технологий секвенирования позволили идентифицировать большое количество генов, связанных с умственной отсталостью, включая редкие формы, в частности, ассоциированные с мутациями в гене QRICH1. Синдром Вервери-Брэди (СВБ; MIM# 617982) - редкий синдром с аутосомно-доминантным типом наследования, характеризуется нарушением интеллекта, задержкой речи и легкими дисморфическими чертами лица. Впервые в России представлено клиническое и молекулярное описание двух пациентов с эпилепсией, задержкой развития и речи, мягкими дисморфическими чертами лица. При полноэкзомном секвенировании выявлены варианты нуклеотидной последовательность в гене QRICH1 -миссенс-мутация (c.1711G>A; p. Asp571Asn) и мутация сдвига рамки считывания (c.1963_1964insT; p.Lys655IlefsTer). На сегодняшний день в мире зарегистрировано 38 пациентов с мутациями в гене QRICH1. Recent advances in sequencing technologies have enabled identification of multiple genes associated with intellectual disability disorders, including QRICH1 gene. Ververi-Brady syndrome (VBS; MIM: #617982) is a rare developmental disorder, characterized by mild developmental delay, mildly impaired intellectual development and speech delay and mild dysmorphic facial features. For the first time in Russia, clinical and molecular description of two patients with epilepsy, developmental and speech delay, and mild dysmorphic facial features is presented. The variants nucleotide sequence in QRICH1 gene - missense mutation (c.1711G>A; p. Asp571Asn) and frameshift mutations (c.1963_1964insT; p.Lys655IlefsTer) were detected by whole exome sequencing. To date, thirty-eight individuals have been reported with QRICH1 mutations in the world.

Biomedical support is aimed at provision of the athletes' training at various stages of the training and competition process. Withholding of access to this process due to health problems resulting from hepatitis virus infection is a demanding task. The study was aimed to assess the detection rate of the hepatitis B virus, hepatitis C virus and TT virus infection markers in highly trained athletes. A total of 384 blood serum samples were collected from 240 males and 144 females aged 14–49 (athletes engaged in playing sports, precision sports, technical sports, etc.) within the framework of the multicenter open-label cross-sectional clinical trial. All athletes answered a questionnaire, which included demographic information, characteristics of sports, information about the infection risk factors, information about the fact of past acute viral hepatitis and vaccination. Markers of infection with hepatitis B virus, hepatitis C virus and TTV were identified in blood serum by enzyme immunoassay. HbsAg was detected in two surveyed athletes. Anti-HBcore (surrogate marker of latent HBV infection) was detected in 7% of samples (27/384); 1% of athletes (4/384) had a positive hepatitis C virus total antibody test (anti-HCV). Аnti-HCV in combination with anti-HBcore was detected in one female athlete (14 years of age, tennis player). DNA of TTV, TTMDV and TTMV was detected in blood serum samples of 89.1%, 83.1% and 85.4% of athletes, respectively. High detection rate of the hepatitis virus markers was observed.

Hereditary and congenital pathologies make up a significant proportion in the structure of the general morbidity and mortality of the child population. In this regard, the problem of personalized medical care in multidisciplinary clinical centers seems very urgent. In the Scientific-Practical Center of specialized medical care for children the medical genetic service successfully functions since 1995. In 2017–2019, patients were consulted by geneticists, which accounted for 10,6% of all discharged patients; karyotype studies were performed in 463 (20,4%) consulted patients, chromosomal pathology was revealed in 28 (6,04%) of all karyotyped patients. DNA research was performed in 188 patients: exome sequencing – in 112; sequencing of exons of the SCN1A gene – in 39; search for mutations in the PHOX2B gene – in 17; search for frequent mutations in the FGFR1,2,3 genes – in 15 (the technique was introduced since September 2018); sequencing of SLC2A1 gene – in 5 patients. The high demand for medical genetic counseling and laboratory genetic diagnosis of hereditary and congenital diseases confirms the need for independent medical genetic units in multidisciplinary clinical hospitals, that should interact with medical genetic services at regional and federal levels.

Congenital muscular dystrophies are heterogeneous groups of neuromuscular diseases leading to hypotonia, progressive muscle weakness and dystrophic or structural signs in muscle biopsy. At the present time, 34 genes associated with congenital muscular dystrophy have been described. The clinical case of a rare form of congenital muscular dystrophia associated with a homozygous mutation in the TRIP4 gene in a patient with respiratory failure requiring respiratory support, neurological symptoms, muscular hypotonia, and multiple congenital malformations of skeletal system is presented for the first time in Russia. The undescribed pathogenic homozygous variant of the nucleotide sequence in the TRIP4 gene (chr15:64686179, c.136C>T, p.Arg46Ter, 2 exon, NM_016213.4) was detected by whole exome sequencing. The mutation in the TRIP4 gene was validated by Sanger sequencing in a child and its origin was investigated. The mother and father of the girl are carriers of the heterozygous variant in the TRIP4 gene. Identification of the genetic cause of a rare form of neuromuscular disease is important for determining the tactics of patient management and medical and genetic counseling of the family, as well as clarifying the pathogenesis of a rare pathology.

We present the clinical case of patient with epilepsy, developmental retardation and hearing loss. The whole exome sequencing allowed to reveal compound heterozygous variants of the nucleotide sequence in SPATA5 gene (c.1714+1G>A, c.1678G>A). Mutations in the SPATA5 gene have been described in patients with epilepsy, hearing loss and mental retardation syndrome (MIM 616577). Paired parents were carriers of one heterozygous gene variant. Such mutations lead to the development of epileptic disorders in 3% of cases, and should be considered in patients not only as a possible cause of neurodegenerative diseases, but also leading to pathology with clinical manifestations mimicking mitochondrial disease.