Nikolay Alekseyevich Skryabin

CHD2-related neurodevelopmental disorders are increasingly recognized as a distinct group of epileptic encephalopathies with heterogeneous clinical manifestations. Here, we report a 12-year-old female patient with pharmacoresistant epilepsy, mild cognitive impairment (IQ = 56), and extraneurological features including grade II kyphoscoliosis and planovalgus foot deformity. Video-EEG monitoring revealed a phenotype consistent with Jeavons syndrome, characterized by daily eyelid myoclonia with absences and marked photosensitivity with an eye closure sensitivity (ECS) phenomenon. Molecular genetic testing via whole-exome and Sanger sequencing identified two novel variants in the CHD2 gene (NM_001271.4): c.1634T>G (p.Leu545Arg) and c.3810G>C (p.Leu1270Phe). Long-read nanopore sequencing confirmed their de novo status and cis-positioning on the paternal allele. Structural bioinformatic analysis using AlphaFold3, FoldX/mCSM (v5.0 package), UCSF ChimeraX (v1.10.1), and PyMOL (v3.1.8) demonstrated that both variants individually destabilize the CHD2 protein, with a cumulative destabilizing effect when combined: p.Leu545Arg affects the ATP-binding domain, whereas p.Leu1270Phe disrupts hydrophobic packing within the C-terminal DNA-binding domain. These findings suggest accelerated protein degradation as a potential disease mechanism. Our data support the pathogenicity of these heterozygous cis-variants and implicate CHD2 haploinsufficiency as the leading etiopathogenic mechanism, though distinct domain-specific effects of each substitution may also contribute to the complex molecular synergy observed in this case.

The XIAP gene (also known as BIRC4) encodes the XIAP protein, which belongs to the inhibitor of apoptosis (IAP) family of proteins and demonstrates potent anti-apoptotic properties. XIAP is also involved in different intracellular signaling pathways, including the NF-κB pathway, the c-Jun N-terminal kinase pathway, and the TGF-β pathway. Disturbances in the expression and function of XIAP are primarily linked to the development of X-linked lymphoproliferative syndrome type 2, Crohn’s disease, neurodegenerative disorders, and the cancer pathogenesis. The role of XIAP in pathological processes remains an area of intensive research. This review summarizes current understanding of XIAP-mediated pathological processes and presents data on the potential for targeted therapy.

Background. Neurofibromatosis type 1 is a common hereditary autosomal dominant disorder caused by pathogenic genetic variants in the NF1 gene located on chromosome 17q11.2. The disease is characterized by high allelic heterogeneity and the absence of clear genotypic correlations, with the exception of large deletions associated with a more severe phenotype. Clinically, neurofibromatosis is characterized by the presence of multiple (≥6) ‟café-au-lait” spots, neurofibromas of any type or plexiform neurofibromas, freckles in the axillary or inguinal areas, hamartomatous Lisch nodules of the iris, optic glioma, and bone dysplasia. Therefore, the description of each new genetic variant is essential for expanding the spectrum of known variants and improving molecular diagnostics. Case Report. The article describes a clinical and molecular genetic study of a 10-year-old boy. Since early childhood, the patient has had multiple “café-au-lait” spots, speech impairment, grade 1 hypotrophy, rickets, sequelae of perinatal CNS damage, myotonic syndrome, and a delay in motor development. Magnetic resonance imaging of the brain revealed signs of focal damage to both hemispheres, the cerebellar vermis, and the left subcortical nuclei, and a glioma of the right optic nerve was detected. Neurofibromatosis type 1 was diagnosed based on clinical criteria. Whole-genome DNA sequencing was performed, followed by bioinformatics analysis and confirmation of the results by direct Sanger sequencing. A previously undescribed complex, likely pathogenic variant NM_001042492.3:c.40 60_4068delinsC of the NF1 gene was identified in the heterozygous state. This variant leads to a reading frameshift and premature translation termination after the synthesis of 23 amino acids (p.Ser1354Leufs*23). This variant is not present in available population genetic variant databases. Conclusion. Thus, whole-genome sequencing identified a new pathogenic variant in the NF1 gene associated with the development of neurofibromatosis type 1. The obtained data expand the range of variants for this pathology and can be used in medical genetic counseling, as well as in algorithms for molecular genetic diagnostics of patients with suspected neurofibromatosis type 1.

Schizophrenia is a chronic, progressive, and multifactorial disorder that leads to significant disability and social maladaptation in patients. Although considerable progress has been made in research, the etiology and pathogenesis of schizophrenia remain incompletely understood. However, the involvement of genetic factors in the development of this disease has been established. Using the GWAS catalog, we identified variants within the TCF4 gene that showed a significant association with schizophrenia. The GWAS catalog lists 30 variants within the TCF4 gene associated with schizophrenia. Among these, 12 variants demonstrate a specific association with schizophrenia in the absence of reported comorbidities. The presence and allele frequencies of these variants were subsequently analyzed in two population databases: Database of Population Frequencies of Genetic Variants in the Russian Federation (DPF) and gnomAD. For the functional annotation of the genetic variants, we utilized specialized tracks within the UCSC Genome Browser. The CpG Islands track served to identify potential regulatory regions. The GeneHancer database was used to predict SNP localization within enhancer regions and their potential target genes. To characterize the epigenetic landscape and functional chromatin states, the ENCODE Regulation and ENCODE cCREs tracks were utilized. Comparative analysis revealed significant heterogeneity in the allele and genotype frequencies of TCF4 polymorphisms between the Russian population and other global cohorts. This observed inter-ethnic variability may partly explain the discrepant genetic association findings for schizophrenia reported across different ancestral groups. Therefore, further functional studies are essential to define the precise mechanisms by which TCF4 variants contribute to disease pathogenesis.

Palmoplantar keratoderma is a clinically polymorphic disease with heterogenous etiology characterized by pronounced hyperkeratotic changes on the surface of the palms and soles. Hereditary forms of palmoplantar keratoderma are predominantly described by various variants in genes belonging to keratin family with autosomal dominant inheritance. A familial case of palmoplantar keratoderma is described. The analysis of family tree suggested autosomal dominant inheritance. Clinical manifestations included hyperkeratosis, xeroderma especially on the skin of the palms and feet: skin thickening with peeling and cracks, smoothed skin pattern. A previously undescribed and probably pathogenic c.103T>G variant of the AQP5 gene in heterozygous state in the proband, her mother and maternal grandfather was revealed as a result of whole genome sequencing. The presented clinical case is of interest for dermatologists due to the occasional incidence of palmoplantar keratoderma caused by variants in the AQP5 gene in clinical practice. Thus, the following diagnosis was established depending on the anamnestic data, clinical picture and examination results in the family: Bothnian palmoplantar keratoderma caused by a probably pathogenic variant in the AQP5 gene.

Marfan syndrome is a hereditary connective tissue disorder characterized by marked pleiotropy and clinical variability. The main disease manifestations involve three systems: skeletal, ocular, and cardiovascular. The condition is caused by pathogenic variants in the FBN1 gene, which encodes fibrillin-1, a protein essential for the formation and maintenance of the extracellular matrix. This article describes a familial case (the proband and his father) with clinical manifestations of Marfan syndrome. Whole-genome sequencing of the proband and his father revealed a previously unreported variant, c.5782TA, p.(Cys1928Ser), in the FBN1 gene. Thus, a molecular genetic diagnosis of Marfan syndrome was established by identifying this novel pathogenic variant. Conclusion. A confirmed diagnosis at both the clinical and molecular genetic levels in both patients determines the further therapeutic strategy and enables timely primary and secondary disease prevention within the family.

Cellular plasticity, a critical feature of embryonic development, is often reactivated in cancer, enabling tumor cells to acquire stem-like properties and facilitate uncontrolled growth. This study compares cellular plasticity in cancer and early human development by integrating single-cell data from three cancers and embryoid bodies. The analysis identifies a shared, highly proliferative progenitor-like state, driven by an E2F-TFDP transcriptional axis and enriched in key cell-cycle regulators UBE2C , TOP2A , BIRC5 , and NUSAP1 . Functionally linked to cell-cycle progression and DNA repair, this state acts as a lineage hub within tumors. Spatial transcriptomics revealed that this state is enriched in lung adenocarcinoma and in lung tissue with basal cell hyperplasia, a potential precursor to squamous cell carcinoma. Validation across eight cancer types demonstrates a prevalence of this program in tumors versus normal cells. Collectively, these findings define a conserved mechanism of tumor plasticity with potential for early detection and targeted therapy. Abstract Figure:

Preimplantation genetic testing for structural rearrangements (PGT-SR) is critical for embryo selection. Most advanced PGT-SR platforms rely on sequence- or marker-based analysis near chromosomal breakpoints, which is costly, labor-intensive, and time-consuming. As a result, clinical practice often defaults to using PGT-A, a platform that cannot detect balanced rearrangements affecting the offspring's reproductive potential. In this study, we introduce Biop-C, a Hi-C–based technique enabling the comprehensive detection of both unbalanced and balanced translocations, including Robertsonian ones, as well as copy number variations (CNV). By developing custom algorithms for translocation detection, we achieved high accuracy in embryo and biopsy samples. We show that using machine-learning-based approaches allows detecting CNVs using low-coverage Hi-C without control euploid human embryos, which are typically unavailable. In a cohort of over 100 samples, Biop-C delivered ploidy status concordant with standard PGT for 93% of embryos and 76% re-biopsies. Out of 36 samples derived from patients carrying balanced chromosomal rearrangements, Biop-C correctly identified 83% translocations: 15 unbalanced and 4 balanced. Notably, Biop-C identified an unbalanced translocation t(18;21) in an embryo derived from a couple with a previously undiagnosed parental translocation 46,XY,t(18;21)(q22.1;q21.3), demonstrating its diagnostic value. These findings establish Biop-C as a powerful PGT-SR approach for distinguishing between normal and balanced embryos, with significant implications for embryo selection and genetic counseling in IVF.

The role of the genetic component in the development of schizophrenia and the formation of its clinical heterogeneity has been proven. To conduct a pilot associative analysis between positive and negative schizophrenia symptoms and polymorphic variants of the Transcription Factor 4 (TCF4) gene. The study included 373 patients with schizophrenia of Caucasian ethnicity, who underwent a comprehensive clinical examination, and a control group consisted of 194 mentally and somatically healthy individuals. Genotyping of three polymorphic variants of the TCF4 gene was carried out in the studied samples (rs2958182, rs8766, and rs9636107). Statistical analysis of the results was performed using Statistica for Windows V.12.0. Association analysis in SNPs was conducted using the chi-square criterion and Bonferroni correction. Groups of schizophrenia patients and healthy individuals were compared for selected TCF4 gene polymorphisms. No statistically significant differences in genotype and allele frequencies were found. The AA genotype and the A allele of the rs2958182 polymorphic variant, as well as the A allele of the rs9636107 polymorphic variant, had an effect predisposing to the predominance of negative symptoms. The TT genotype and the T allele of the rs2958182 polymorphic variant, as well as the G allele of the rs9636107 polymorphic variant, were statistically significantly more common among patients with leading positive symptoms. As a result of the study, associations of the polymorphic variant TCF4 rs2958182 and TCF4 rs9636107 with the leading symptoms of schizophrenia were discovered for the first time in Caucasian populations of the Siberian region. The obtained data confirm the contribution of the genetic component to the formation of clinical heterogeneity of schizophrenia and open up prospects for further search for genetic markers in order to prevent an unfavorable outcome of the disease.

Pycnodysostosis (PD) is a rare autosomal recessive skeletal dysplasia from impaired bone resorption due to osteoclastic dysfunction. The features of PD are deformity of the skull, maxilla, and phalanges; osteosclerosis; and bone fragility. We describe the case of a patient with complaints of multiple fractures of the lower extremities in the anamnesis and pain in the lower extremities, cervical spine, and shoulder girdle during physical exertion. Genetic testing revealed a novel homozygous variant c.704T>C (p.Leu235Pro) in the CTSK gene. Biallelic pathogenic variants in this gene lead to PD. Thus, the diagnosis in the patient was established by finding a novel likely pathogenic variant in the CTSK gene.