In the past decade, numerous studies have made connections between sequence variants in human genomes and predisposition to complex diseases. However, most of these variants lie outside of the charted regions of the human genome whose function we understand; that is, the sequences that encode proteins. Consequently, the general concept of a mechanism that translates these variants into predisposition to diseases has been lacking, potentially calling into question the validity of these studies. Here we make a connection between the growing class of apparently functional RNAs that do not encode proteins and whose function we do not yet understand (the so-called ‘dark matter’ RNAs) and the disease-associated variants. We review advances made in a different genomic mapping effort – unbiased profiling of all RNA transcribed from the human genome – and provide arguments that the disease-associated variants exert their effects via perturbation of regulatory properties of non-coding RNAs existing in mammalian cells.

Familial dysbetalipoproteinemia (FD) is a highly atherogenic genetically based lipid disorder with an underestimated actual prevalence. In recent years, several biochemical algorithms have been developed to diagnose FD using available laboratory tests. The practical applicability of FD diagnostic criteria and the prevalence of FD in Russia have not been previously assessed. We demonstrated that the diagnostic algorithms of FD, including the diagnostic apoB levels, require correction, taking into account the distribution of apoB levels in the population. At the same time, a triglycerides cutoff ≥ 1.5 mmol/L may be a useful tool in identifying subjects with FD. In this study, a high prevalence of FD was detected: 0.67% (one in 150) based on the ε2ε2 haplotype and triglycerides levels ≥ 1.5 mmol/L. We also analyzed the presence and pathogenicity of APOE variants associated with autosomal dominant FD in a large research sample.

Left ventricular noncompaction (LVNC) is a highly heterogeneous primary disorder of the myocardium. Its clinical features and genetic spectrum strongly overlap with other types of primary cardiomyopathies, in particular, hypertrophic cardiomyopathy. Study and the accumulation of genotype–phenotype correlations are the way to improve the precision of our diagnostics. We present a familial case of LVNC with arrhythmic and thrombotic complications, myocardial fibrosis and heart failure, cosegregating with the splicing variant in the FHOD3 gene. This is the first description of FHOD3-dependent LVNC to our knowledge. We also revise the assumed mechanism of pathogenesis in the case of FHOD3 splicing alterations.

The Colorado potato beetle (CPB) is one of the most serious insect pests due to its high ecological plasticity and ability to rapidly develop resistance to insecticides. The use of biological insecticides based on viruses is a promising approach to control insect pests, but the information on viruses which infect leaf feeding beetles is scarce. We performed a metagenomic analysis of 297 CPB genomic and transcriptomic samples from the public National Center for Biotechnology Information Sequence Read Archive (NCBI SRA) database. The reads that were not aligned to the reference genome were assembled with metaSPAdes, and 13314 selected contigs were analyzed with BLAST tools. The contigs and non-aligned reads were also analyzed with Kraken2 software. A total of 3137 virus-positive contigs were attributed to different viruses belonging to 6 types, 17 orders, and 32 families, matching over 97 viral species. The annotated sequences can be divided into several groups: those that are homologous to genetic sequences of insect viruses (Adintoviridae, Ascoviridae, Baculoviridae, Dicistroviridae, Chuviridae, Hytrosaviridae, Iflaviridae, Iridoviridae, Nimaviridae, Nudiviridae, Phasmaviridae, Picornaviridae, Polydnaviriformidae, Xinmoviridae etc.), plant viruses (Betaflexiviridae, Bromoviridae, Kitaviridae, Potyviridae), and endogenous retroviral elements (Retroviridae, Metaviridae). Additionally, the full-length genomes and near-full length genome sequences of several viruses were assembled. We also found sequences belonging to Bracoviriform viruses and, for the first time, experimentally validated the presence of bracoviral genetic fragments in the CPB genome. Our work represents the first attempt to discover the viral genetic material in CPB samples, and we hope that further studies will help to identify new viruses to extend the arsenal of biopesticides against CPB.

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders.

Cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss are among the most common autosomal recessive diseases, which require carrier screening. The evaluation of population allele frequencies (AF) of pathogenic variants in genes associated with these conditions and the choice of the best genotyping method are the necessary steps toward development and practical implementation of carrier-screening programs. We performed custom panel genotyping of 3821 unrelated participants from two Russian population representative samples and three patient groups using real-time polymerase chain reaction (PCR) and next generation sequencing (NGS). The custom panel included 115 known pathogenic variants in the CFTR, PAH, SERPINA1, and GJB2 genes. Overall, 38 variants were detected. The comparison of genotyping platforms revealed the following advantages of real-time PCR: relatively low cost, simple genotyping data analysis, and easier detection of large indels, while NGS showed better accuracy of variants identification and capability for detection of additional pathogenic variants in adjacent regions. A total of 23 variants had significant differences in estimated AF comparing with non-Finnish Europeans from gnomAD. This study provides new AF data for variants associated with the studied disorders and the comparison of genotyping methods for carrier screening.