НИИ
медицинской
генетики

Precocious puberty (PP, OMIM 176400, 615346) is an autosomal dominant disorder caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, epigenetic, and environmental factors play a decisive role in determining the timing of puberty. In recent years, genetic variants in the KISS1, KISS1R, MKRN3, and DLK1 genes have been identified as genetic causes of PP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic fications, such as DNA methylation, which alter the expression of these genes, can also contribute to the development of PP. The aim of this study is to determine the methylation index of the imprinting centers of the DLK1 and MKRN3 genes in girls with a clinical presentation of PP. The methylation index of the imprinting centers of the DLK1 and MKRN3 genes was analyzed in a group of 45 girls (age 7.2±1.9 years) with a clinical presentation of PP and a normal karyotype using targeted massive parallel sequencing after sodium bisulfite treatment of DNA. The control group consisted of girls without PP (n = 15, age 7.9±1.6 years). No significant age differences were observed between the groups (p > 0.8). Analysis of the methylation index of the imprinting centers of the DLK1 and MKRN3 genes revealed no significant differences between patients with PP and the control group. However, in the group of patients with isolated adrenarche, an increased methylation index of the imprinting center of the MKRN3 gene was observed (72±7.84 vs 56.92±9.44 %, p = 0.005). In the group of patients with central PP, 3.8 % of patients showed a decreased methylation index of the imprinting center of the DLK1 gene, and 11.5 % of probands had a decreased methylation index of the imprinting center of the MKRN3 gene. Thus, this study demonstrates that not only genetic variants but also alterations in the methylation index of the imprinting centers of the DLK1 and MKRN3 genes can contribute to the development of PP.

Новая коронавирусная инфекция (COVID-19) - острое инфекционное заболевание, вызываемое вирусом SARS-CoV-2. Пандемия COVID-19 стала глобальным вызовом для здравоохранения и науки, а в области генетики человека привела к всплеску исследований роли генетики организма-хозяина в подверженности и тяжести течения инфекционного заболевания. Несмотря на негенетическую этиологию COVID-19, полногеномные ассоциативные исследования и работы по полногеномному и полноэкзомному анализу выявили целый ряд участков генома, достоверно ассоциированных с восприимчивостью к инфекции и тяжестью течения заболевания, модифицирующих риск развития COVID-19 на индивидуальном уровне. Эти данные не могут являться основанием для определения групп риска или прогноза тяжести течения болезни, однако полезны для понимания патогенетики болезни и для разработки подходов к ее диагностике и терапии. Исследования на уровне постгеномных механизмов регуляции реализации генетической информации выявили специфические паттерны экспрессии и метилирования генома в ответе на вирус и в ходе прогрессии заболевания и показали потенциал для разработки таргетных подходов для терапии и профилактики COVID-19. Вызовы для генетики как науки, возникшие с развитием пандемии COVID-19, ответы на них, опыт и накопленные данные, несомненно, найдут отражение в дальнейших обоснованных подходах к диагностике, профилактике и лечению как COVID-19, так и других быстро распространяющихся инфекционных заболеваний.

The novel coronavirus infection (COVID-19) is an acute infectious disease caused by the SARS CoV2 virus. The COVID-19 pandemic has become a global challenge for health and science, and in the field of human genetics, it has led to a surge in research on the role of host genetics in susceptibility to and severity of infectious diseases. Despite the nongenetic etiology of COVID-19, genome-wide association studies and whole-genome and whole-exome analyses have identified a number of genomic regions that are significantly associated with susceptibility to infection and disease severity, modifying the risk of developing COVID-19 at the individual level. These data cannot serve as a basis for identifying risk groups or predicting the severity of the disease, but are useful for understanding the pathogenesis of the disease and developing approaches to its diagnosis and therapy. Studies at the level of post-genomic mechanisms regulating the implementation of genetic information have revealed specific patterns of expression and methylation of the genome in response to the virus and during disease progression and have shown the potential for developing targeted approaches for the treatment and prevention of COVID-19. The challenges for genetics as a science that have arisen with the development of the COVID-19 pandemic, the answers to them, the experience, and accumulated data will undoubtedly be reflected in further substantiated approaches to the diagnosis, prevention, and treatment of both COVID-19 and other rapidly spreading infectious diseases.

Background Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type-whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs).Methods We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Results Applied to 66 human samples Exo-C achieved 100% recall and 73% precision in detecting chromosomal translocations and SNVs. We further benchmarked its performance for inversions and CNVs and demonstrated its utility in detecting mosaic SVs and resolving diagnostically challenging cases. Conclusions Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.