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.

Background The COVID-19 pandemic in Russia has already resulted in 500,000 excess deaths, with more than 5.6 million cases registered officially by July 2021. Surveillance based on case reporting has become the core pandemic monitoring method in the country and globally. However, population-based seroprevalence studies may provide an unbiased estimate of the actual disease spread and, in combination with multiple surveillance tools, help to define the pandemic course. This study summarises results from four consecutive serological surveys conducted between May 2020 and April 2021 at St. Petersburg, Russia and combines them with other SARS-CoV-2 surveillance data. Methods We conducted four serological surveys of two random samples (May-June, July-August, October-December 2020, and February-April 2021) from adults residing in St. Petersburg recruited with the random digit dialing (RDD), accompanied by a telephone interview to collect information on both individuals who accepted and declined the invitation for testing and account for non-response. We have used enzyme-linked immunosorbent assay Corona-Pass total antibodies test (Genetico, Moscow, Russia) to report seroprevalence. We corrected the estimates for non-response using the bivariate probit model and also accounted the test performance characteristics, obtained from independent assay evaluation. In addition, we have summarised the official registered cases statistics, the number of hospitalised patients, the number of COVID-19 deaths, excess deaths, tests performed, data from the ongoing SARS-CoV-2 variants of concern (VOC) surveillance, the vaccination uptake, and St. Petersburg search and mobility trends. The infection fatality ratios (IFR) have been calculated using the Bayesian evidence synthesis model. Findings After calling 113,017 random mobile phones we have reached 14,118 individuals who responded to computer-assisted telephone interviewing (CATI) and 2,413 provided blood samples at least once through the seroprevalence study. The adjusted seroprevalence in May-June, 2020 was 9.7% (95%: 7.7-11.7), 13.3% (95% 9.9-16.6) in July-August, 2020, 22.9% (95%: 20.3-25.5) in October-December, 2021 and 43.9% (95%: 39.7-48.0) in February-April, 2021. History of any symptoms, history of COVID-19 tests, and non-smoking status were significant predictors for higher seroprevalence. Most individuals remained seropositive with a maximum 10 months follow-up. 92.7% (95% CI 87.9-95.7) of participants who have reported at least one vaccine dose were seropositive. Hospitalisation and COVID-19 death statistics and search terms trends reflected the pandemic course better than the official case count, especially during the spring 2020. SARS-CoV-2 circulation showed rather low genetic SARS-CoV-2 lineages diversity that increased in the spring 2021. Local VOC (AT.1) was spreading till April 2021, but B.1.617.2 substituted all other lineages by June 2021. The IFR based on the excess deaths was equal to 1.04 (95% CI 0.80-1.31) for the adult population and 0.86% (95% CI 0.66-1.08) for the entire population. Conclusion Approximately one year after the COVID-19 pandemic about 45% of St. Petersburg, Russia residents contracted the SARS-CoV-2 infection. Combined with vaccination uptake of about 10% it was enough to slow the pandemic at the present level of all mitigation measures until the Delta VOC started to spread. Combination of several surveillance tools provides a comprehensive pandemic picture.

This study provides new data on the whole-exome sequencing of a cohort of children with autistic spectrum disorders (ASD) from an underexplored Russian population. Using both a cross-sectional approach involving a control cohort of the same ancestry and an annotation-based approach involving relevant public databases, we explored exonic single nucleotide variants and copy-number variation potentially involved in the manifestation of ASD. The study results reveal new potential ASD candidate-variants found in the studied Russian cohort and show a high prevalence of common ASD-associated genomic variants, especially those in the genes known to be associated with the manifestation of intellectual disabilities. Our screening of an ASD cohort from a previously understudied population allowed us to flag at least a few novel genes (IGLJ2, FAM21A, OR11H12, HIP1, PRAMEF10, and ZNF717) regarding their potential involvement in ASD.

Introduction: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological syndrome caused by pathogenic variants in the C19orf12 and is characterized by iron deposition in the basal ganglia and substantia nigra. Only a limited number of cohort studies were published to date and the prevalence of MPAN remains uncertain. Methods: Recruited subjects with MPAN in Russia were diagnosed by whole-exome sequencing or Sanger sequencing of the C19orf12 gene. Data of over 14000 whole exome sequencing analyses was used to calculate the estimated disease frequency. RNA analysis was performed by RT-PCR. QSVanalyzer software was used to quantify the allelic disbalance. Results: We describe the clinical and molecular characterizations of 17 patients with MPAN. DNA analysis detected three previously undescribed pathogenic/likely pathogenic variants in the C19orf12 gene. The esti-mated disease frequency was calculated to be 1:619150. We describe unusual clinical observations in several cases. One patient showed severe neurogenic muscle weakness along with a lack of marked spasticity or optic nerve atrophy. In another mild clinical case with the NM_001031726.3:c.204_214del (p.(Gly69Argfs*10)) variant in a heterozygous state, a marked allelic disbalance was observed on the RNA level with reduced expression level of the wild-type allele. Thus, this case became the first one of a possible regulatory variant causing MPAN. Conclusion: We reported a detailed clinical and molecular characterization of the third-largest MPAN cohort. We expanded the mutational and clinical spectrum of MPAN. Moreover, we calculated the estimated MPAN fre-quency in the Russian population for the first time.

Background The COVID-19 pandemic in Russia has already resulted in 500,000 excess deaths, with more than 5.6 million cases registered officially by July 2021. Surveillance based on case reporting has become the core pandemic monitoring method in the country and globally. However, population-based seroprevalence studies may provide an unbiased estimate of the actual disease spread and, in combination with multiple surveillance tools, help to define the pandemic course. This study summarises results from four consecutive serological surveys conducted between May 2020 and April 2021 at St. Petersburg, Russia and combines them with other SARS-CoV-2 surveillance data. Methods We conducted four serological surveys of two random samples (May–June, July–August, October–December 2020, and February–April 2021) from adults residing in St. Petersburg recruited with the random digit dialing (RDD), accompanied by a telephone interview to collect information on both individuals who accepted and declined the invitation for testing and account for non-response. We have used enzyme-linked immunosorbent assay CoronaPass total antibodies test (Genetico, Moscow, Russia) to report seroprevalence. We corrected the estimates for non-response using the bivariate probit model and also accounted the test performance characteristics, obtained from independent assay evaluation. In addition, we have summarised the official registered cases statistics, the number of hospitalised patients, the number of COVID-19 deaths, excess deaths, tests performed, data from the ongoing SARS-CoV-2 variants of concern (VOC) surveillance, the vaccination uptake, and St. Petersburg search and mobility trends. The infection fatality ratios (IFR) have been calculated using the Bayesian evidence synthesis model. Findings After calling 113,017 random mobile phones we have reached 14,118 individuals who responded to computer-assisted telephone interviewing (CATI) and 2,413 provided blood samples at least once through the seroprevalence study. The adjusted seroprevalence in May–June, 2020 was 9.7% (95%: 7.7–11.7), 13.3% (95% 9.9–16.6) in July–August, 2020, 22.9% (95%: 20.3–25.5) in October–December, 2021 and 43.9% (95%: 39.7–48.0) in February–April, 2021. History of any symptoms, history of COVID-19 tests, and non-smoking status were significant predictors for higher seroprevalence. Most individuals remained seropositive with a maximum 10 months follow-up. 92.7% (95% CI 87.9–95.7) of participants who have reported at least one vaccine dose were seropositive. Hospitalisation and COVID-19 death statistics and search terms trends reflected the pandemic course better than the official case count, especially during the spring 2020. SARS-CoV-2 circulation showed rather low genetic SARS-CoV-2 lineages diversity that increased in the spring 2021. Local VOC (AT.1) was spreading till April 2021, but B.1.617.2 substituted all other lineages by June 2021. The IFR based on the excess deaths was equal to 1.04 (95% CI 0.80–1.31) for the adult population and 0.86% (95% CI 0.66–1.08) for the entire population. Conclusion Approximately one year after the COVID-19 pandemic about 45% of St. Petersburg, Russia residents contracted the SARS-CoV-2 infection. Combined with vaccination uptake of about 10% it was enough to slow the pandemic until the Delta VOC started to spread. Combination of several surveillance tools provides a comprehensive pandemic picture. Funding Polymetal International plc.

Hurdle count models are used to examine the participation and consumption decisions in Chinese medicine use. Motivated by a household production model, a second censoring mechanism is introduced into existing single-hurdle models, and the resulting specification accommodates conscientious abstainers, as well as economic non-consumers, and admits excessive zeros in the sample. In contrast to previous studies that found few predictors, empirical results based on a Taiwanese national sample suggest that Western medicine is a gross substitute to Chinese medicine, and both time price and money price play more important roles than income. Insurance, lifestyle and demographics also determine the use of Chinese medicine.

Jansen-de Vries syndrome is a rare hereditary autosomal dominant disease caused by pathogenic variants in the PPM1D gene. To date, 18 cases of this syndrome have been described in the world. In all cases, heterozygous mutations were identified that arose de novo in the last or penultimate exons of the gene, leading to protein truncation. All observed patients had muscle hypotonia, delayed motor and speech development, intellectual and behavioral disorders, an increased pain threshold, and a peculiar phenotype. Objective of the research: to reveal clinical genetic signs of new cases of a rare syndromic form and to identify additional clinical and laboratory features that characterize Jansen-de Vries syndrome. The article presents observations of two patients with Jansen-de Vries syndrome, first diagnosed in the Russian Federation. Children underwent routine laboratory and instrumental examinations, repeated consultations with a neurologist, geneticist, ophthalmologist, cardiologist and orthopedist. The diagnosis was made by full exome sequencing. A comparison of the identified cases with those described in the literature is performed. The observed girls from two unrelated families showed characteristic clinical manifestations, as in patients previously presented in the foreign literature: muscle hypotension, delayed motor and psycho-speech development, small hands and feet. Additionally, the first child had a prolonged course of neonatal meningitis and a low level of immunoglobulin A, the second had unilateral ptosis, congenital stridor. The de novo mutations found were confirmed by Sanger sequencing. A previously undescribed pathogenic variant c.1225del (p.Met409Ter) in the penultimate exon of the PPM1D gene was detected in the first child of 10 months. In the second child, a previously established pathogenic variant c.1270dupG (p.Glu424fs) was found in the last exon of this gene. Conclusion: the work presents the first domestic observations confirming the presence of characteristic clinical and genetic manifestations of the Jansen-de Vries syndrome. In addition, a previously undescribed pathogenic variant c.1225del (p.Met409Ter) was revealed in the penultimate exon of the PPM1D gene. In one of the observed children, features of humoral immunity were found, which may also be characteristic of this pathology.

The frequency of a genetic variant in a population is crucially important for accurate interpretation of known and novel variant effects in medical genetics. Recently, several large allele frequency databases, such as Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency can be more informative than the global one. Many countries and regions (including Russia) remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct an expanded reference set of genetic variants by analyzing 6,096 exome samples collected in two major Russian cities of Moscow and St. Petersburg. An approximately tenfold increase in sample size compared to previous studies allowed us to identify genetically distinct clusters of individuals within an admixed population of Russia. We show that up to 18 known pathogenic variants are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite either being annotated as pathogenic in ClinVar or falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at http://ruseq.ru.

Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In this article, we report a novel molecular genetic cause of Pompe disease, which could be hardly detected using routine molecular genetic analysis. Whole genome sequencing followed by comprehensive functional analysis allowed us to discover and characterize a complex mobile genetic element insertion deep in the intron 15 of the GAA gene in a patient with infantile onset Pompe disease.

The human induced pluripotent stem cell (iPSC) lines, iCS-MAF1-1 and iCS-MAF1-11, were generated from fibroblasts. The donor has a heterozygous mutation in the VPS13B gene, which manifests in her child as Cohen syndrome. It is a Golgi pathology, characterized by postnatal microcephaly and delayed growth and mental development. However, the process underlying pathological changes leading to the onset of the disease is still unknown. The use of iPSC will allow describing the early stages of neurogenesis, which is undoubtedly relevant for identifying key stages of development, at which phenotypic manifestations of mutations in the VPS13B gene are found.

Early epileptic encephalopathy-66 was first diagnosed in a male patient from Russia using whole-exome sequencing. Early epileptic encephalopathy- 66 is a unique disorder in the group of early epileptic encephalopathies. The same recurrent heterozygous variant of the nucleotide sequence was found in all known patients, but the severity of seizures and dysmorphic signs significantly vary between patients. The current study of a recurrent pathogenic variant in PACS2 gene expands the phenotype spectrum of early epileptic encephalopathy-66 and will improve the management of patients with that disorder in Russia in the future.

M.E. Ivanova1, V.V. Kadyshev2, D.S. Atarshchikov3, I.V. Zolnikova4, N.P. Akchurina4, N.K. Serova5, F.A. Konovalov6, E.R. Lozier6, E.A. Pomerantseva7, N.V. Vetrova7, D. Barh8, L.M. Balashova9, J.M. Salmasi10 1 LLC “Oftalmic”, Moscow, Russian Federation 2 Research Centre for Medical Genetics, Moscow, Russian Federation 3 Central Clinical Hospital under Presidential Affairs, Moscow, Russian Federation 4 Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russian Federation 5 N.N. Burdenko National Medical Research Center of Neurosurgery, Moscow, Russian Federation 6 Independent Clinical Bioinformatics Laboratory, Moscow, Russian Federation 7 Center for Genetics and Reproductive Medicine “Genetiko”, Moscow, Russian Federation 8 Institute of Integrative Omics and Applied Biotechnology (IIOAB), Bangalore, India 9 Non-profit partnership International Scientific and Practical Center for the Proliferation of Tissues of Russia, Moscow, Russian Federation 10Pirogov Russian National Research Medical University, Moscow, Russian Federation The article describes the clinical case of optic atrophy due to a homozygous mutation in exon 3 of the C19orf12 gene (chr19: 30193863AACAGCCCCCCG> A, rs515726204), the frequency of which in the ExAC control sample is 0.0074. With this mutation, a frameshift occurs at 69-th position (p.Gly69fs, NM_001031726.3), which usually leads to neurodegeneration with the brain iron accumulation (NBIA), type 4 (OMIM: 614298). In described clinical case the main complaint of patient was visual impairment, with magnetic resonance imaging patient revealed only the expansion of the sellar fossa. The vision of 7-year-old boy decreased significantly for 2 years without any apparent reasons, spectacle correction did not give an improvement in vision to 100%. During the examination partial atrophy of the optic nerves was revealed, consultations were conducted with a neurologist, neurophthalmologist. Hyperreflexia, gait changes, and a slight delay in speech development were also revealed. No other clinical neurological symptoms were observed. The article describes a detailed ophthalmic clinical picture, discusses diagnostic and therapeutic tactics. Keywords: optic nerve atrophy, neurodegeneration with the brain iron accumulation, NBIA, mutation, gene, C19orf12. For citation: Ivanova M.E., Kadyshev V.V., Atarshchikov D.S. et al. Case of phenotype of optic nerve atrophy due to mutation in С19orf12 gene (neurodegeneration with the brain iron accumulation (nbia)). Russian Journal of Clinical Ophthalmology. 2020;20(1):–36. DOI: 10.32364/2311-7729-2020-20-1-33-36.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Objectives: Mutations in the neuroblastoma-amplified sequence (NBAS) gene were originally described in patients with skeletal dysplasia or isolated liver disease of variable severity. Subsequent publications reported a more complex phenotype. Among multisystemic clinical symptoms, we were particularly interested in the immunological consequences of the NBAS deficiency. Methods: Clinical and laboratory data of 3 patients ages 13, 6, and 5 in whom bi-allelic NBAS mutations had been detected via next-generation sequencing were characterized. Literature review of 23 publications describing 74 patients was performed. Results: We report three Russian patients with compound heterozygous mutations of the NBAS gene who had combined immunodeficiency characterized by hypogammaglobulinemia, low T-cells, and near-absent B-cells, along with liver disease, skeletal dysplasia, optic-nerve atrophy, and dysmorphic features. Analysis of the data of 74 previously reported patients who carried various NBAS mutations demonstrated that although the most severe form of liver disease seems to require disruption of the N-terminal or middle part of NBAS, mutations of variable localizations in the gene have been associated with some form of liver disease, as well as immunological disorders. Conclusions: NBAS deficiency has a broad phenotype, and referral to an immunologist should be made in order to screen for immunodeficiency.

Despite the acceptance of NextGen sequencing as a diagnostic modality suitable for probands and carriers of Mendelian diseases, its efficiency in identifying causal mutations is limited by both technical aspects of variant call algorithms and by imperfect, consensus-based criteria for assessing the pathogenicity of the findings. Here we describe the medical history of the family with a child born with Fanconi anemia. In this case, typical diagnostic routines were complicated by unusual combination of mutations. PALB2 variant NM_024675.3:c.172_175delTTGT (p.Gln60Argfs) in maternal sample, previously classified as a definitely pathogenic frameshift mutation, was in compound heterozygous state with PALB2 NM_024675.3:c.3114-16_3114-11del (p.Asn1039Glyfs*7), which led to validated PALB2 exon 11 skipping event in paternal locus. Findings enabled the development of the PGТ and successful selection of two mutation-free embryos. We show that even in absence of definitive exome findings, clinician-guided research inquiries into the structure and function of the suspected loci allow definitive diagnosis. Described case provides an example of a crucial input of an investigational workflow in genetic prognosis and successful PGT.