Trisomy is the presence of one extra copy of an entire chromosome or its part in a cell nucleus. In humans, autosomal trisomies are associated with severe developmental abnormalities leading to embryonic lethality, miscarriage or pronounced deviations of various organs and systems at birth. Trisomies are characterized by alterations in gene expression level, not exclusively on the trisomic chromosome, but throughout the genome. Here, we applied the high-throughput chromosome conformation capture technique (Hi-C) to study chromatin 3D structure in human chorion cells carrying either additional chromosome 13 (Patau syndrome) or chromosome 16 and in cultured fibroblasts with extra chromosome 18 (Edwards syndrome). The presence of extra chromosomes results in systematic changes of contact frequencies between small and large chromosomes. Analyzing the behavior of individual chromosomes, we found that a limited number of chromosomes change their contact patterns stochastically in trisomic cells and that it could be associated with lamina-associated domains (LAD) and gene content. For trisomy 13 and 18, but not for trisomy 16, the proportion of compacted loci on a chromosome is correlated with LAD content. We also found that regions of the genome that become more compact in trisomic cells are enriched in housekeeping genes, indicating a possible decrease in chromatin accessibility and transcription level of these genes. These results provide a framework for understanding the mechanisms of pan-genome transcription dysregulation in trisomies in the context of chromatin spatial organization.

Bi-allelic pathogenic variations within POLR3A have been associated with a spectrum of hereditary disorders. Among these, a less frequently observed condition is Wiedemann–Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome. This syndrome typically manifests neonatally and is characterized by growth retardation, evident generalized lipodystrophy with distinctively localized fat accumulations, sparse scalp hair, and atypical facial features. Our objective was to elucidate the underlying molecular mechanisms of Wiedemann–Rautenstrauch syndrome (WRS). In this study, we present a clinical case of a 7-year-old female patient diagnosed with WRS. Utilizing whole-exome sequencing (WES), we identified a novel missense variant c.3677T>C (p.Leu1226Pro) in the POLR3A gene (NM_007055.4) alongside two cis intronic variants c.1909+22G>A and c.3337-11T>C. Via the analysis of mRNA derived from fibroblasts, we reconfirmed the splicing-affecting nature of the c.3337-11T>C variant. Furthermore, our investigation led to the reclassification of the c.3677T>C (p.Leu1226Pro) variant as a likely pathogenic variant. Therefore, this is the first case demonstrating the molecular genetics of a patient with Wiedemann–Rautenstrauch syndrome from the Russian Federation. A limited number of clinical cases have been documented until this moment; therefore, broadening the linkage between phenotype and molecular changes in the POLR3A gene will significantly contribute to the comprehensive understanding of the molecular basis of POLR3A-related disorders.

Here, we report the pediatric cases of sitosterolemia, a rare autosomal-recessive genetic disorder, characterized by high concentrations of plant sterols in blood and heterogeneity manifestations. All three patients (two girls aged 2 and 6 years old, and one boy aged 14 years old) were initially diagnosed with hypercholesterinemia. Next-generation sequencing (NGS) revealed homozygous (p.Leu572Pro/p.Leu572Pro) and compound (p.Leu572Pro/p.Gly512Arg and p.Leu572Pro/p.Trp361*) variants in the ABCG8 gene that allowed for the diagnosis of sitosterolemia. Two patients whose blood phytosterol levels were estimated before the diet demonstrated high levels of sitosterol/campesterol (69.6/29.2 and 28.3/12.4 μmol/L, respectively). Here, we demonstrate that NGS-testing led to the proper diagnosis that is essential for patients’ management. The variant p.Leu572Pro might be prevalent among patients with sitosterolemia in Russia.

Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM_052968: c.579_592delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM_000237.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease.

Sitosterolemia (phytosterolemia) is an inherited metabolic disorder characterized by the accumulation of plant sterols (phytosterols). The disease is caused by loss-of-function genetic mutations in sterolin proteins, which play an important role in selective excretion of plant sterols. Patients exhibit increased serum levels of phytosterols, total cholesterol and low-density lipoprotein cholesterol, which is accompanied by the risk of pre-mature atherosclerosis. Patients can have severe sitosterolemia when xanthomatosis develops as early as in infancy. Hematological disorders in the form of macrothrombocytopenia, stomatocytosis, episodes of hemolysis are reported in patients with sitosterolemia, which can be the only manifestation of the disease and are often interpreted as a manifestation of immune thrombocytopenia or primary hemolytic anemia. Hepatoand splenomegaly, acute liver failure, arthralgia may also be seen. Due to the similarity of clinical phenotypes, sitosterolemia can be misdiagnosed as familial hypercholesterolemia. It is vitally important to perform differential diagnosis to distinguish it from such diseases as lecithin-cholesterol acyltransferase deficiency, Tangier disease, cerebrotendinous xanthomatosis, familial dysbetalipoproteinemia, lysosomal acid lipase deficiency, primary biliary cirrhosis, storage diseases. The treatment of sitosterolemia in children includes the use of the intestinal cholesterol/phytosterol absorption inhibitor ezetimibe and bile acid sequestrant cholestyramine. The effective use of the combination of these drugs is described. The partial bypass of the distal ileum where the absorption of cholesterol, phytosterols, and reabsorption of bile acids mainly occurs can be used in severe cases. For patients with advanced vascular atherosclerosis and resistance to the standard treatments, LDL-C apheresis could be considered. The article describes our own clinical observation of a five-year-old patient suffering from sitosterolemia.