With the development of modern next generation sequencing based DNA diagnostic methods, it has become possible to study hereditary predisposition to oncohematological diseases. Germline variants (mutations) of RUNX1, CEBPA, GATA2, ANKRD26, DDX41, FANC- (Fanconi anemia), etc. genes, associated with the development of hereditary hematological malignancies, have been identified. Timely diagnosis of such diseases will allow for medical genetic counseling and testing of the patient’s relatives to identify or exclude the risk of developing the disease, select a donor for the patient (it is undesirable to use a mutation carrier relative as a donor), and personalize the choice of chemotherapy regimens (for example, patients with Fanconi anemia may experience increased sensitivity to chemotherapy). The aim of this review is to present a modern view of the genetic predisposition to the development of hematological malignancies.

Сегодня результаты развития геномных технологий меняют подход к диагностике и лечению онкологических заболеваний. Так, клинические подходы к профилактике, диагностике и лечению рака молочной железы сместились в сторону использования молекулярно-генетической и иммуногистохимической информации. Целью настоящего обзора является описание возможностей применения различных молекулярно-генетических исследований опухолевой ткани с целью повышения эффективности лечения рака молочной железы. В обзоре обсуждаются результаты применения современных молекулярных (The Cancer Genome Atlas) и иммуногистохимических (суррогатных) маркеров, обеспечивающих разделение РМЖ по молекулярным подтипам, приведены преимущества и недостатки такого разделения. Представлены основные характеристики современных экспрессионных прогностических тестов, обсуждается целесообразность и сложности применения высокопроизводительного секвенирования, в том числе расширенных мультигенных NGS-панелей в клинической практике. Обзор предназначен для ординаторов и аспирантов, врачей-генетиков и врачей-онкологов, использующих в своей работе результаты современных молекулярно-генетических тестов.

Актуальность. Благодаря непрерывному развитию и совершенствованию генетических методов исследований, расширяется спектр возможных пренатально устанавливаемых хромосомных аномалий. Применение современных молекулярно-генетических методов – неинвазивного пренатального теста (НИПТ) и хромосомного микроматричного анализа (ХМА) – позволяет как заподозрить, так и диагностировать хромосомные перестройки, которые невозможно определить стандартным цитогенетическим исследованием. Пациенты и методы. Представлены два клинических случая хромосомной перестройки у плода. Беременным женщинам выполнен пренатальный скрининг I триместра и полногеномный НИПТ. По показаниям проведена инвазивная пренатальная диагностика (ИПД), полученный материал направлен на цитогенетическое исследование и ХМА. Результаты. По результатам пренатального скрининга I триместра пациентки отнесены в группу высокого риска хромосомной аномалии (ХА) плода в обоих случаях. Высокий риск редких ХА установлен по результатам НИПТ. С согласия пациенток проведена ИПД. По результатам цитогенетических исследований и ХМА определен несбалансированный кариотип с наличием дополнительного генетического материала у плодов. Выводы. Применение современных молекулярно-генетических методов в дополнение к традиционным (пренатальному скринингу I триместра и стандартному цитогенетическому исследованию) позволяет увеличить спектр выявляемых ХА, определяемых пренатально. Background. Due to the continuous development and improvement of genetic research methods, the range of possible prenatally determined chromosomal abnormalities is expanding. The use of modern molecular genetic methods, the noninvasive prenatal testing (NIPT) and chromosomal microarray analysis (CMA), allows both the suspicion and diagnosis of chromosomal rearrangements that cannot be identified by standard cytogenetic testing. Patients and methods. Two clinical cases of fetal chromosomal rearrangement are presented. Pregnant women underwent the first trimester prenatal screening and whole-genome NIPT. When indicated, invasive prenatal diagnosis (IPD) was performed, and the obtained material was sent for cytogenetic examination and CMA. Results. Based on the results of prenatal screening in the first trimester of pregnancy, the patients were assigned to the high-risk group for fetal chromosomal abnormalities (CA) in both cases. A high risk of rare CA was established by the results of NIPT. IPD was performed with the consent of the patients. The results of cytogenetic studies and CMA determined an unbalanced karyotype with the presence of additional genetic material in the fetuses. Conclusions. The use of modern molecular genetic methods in addition to traditional methods (the first trimester prenatal screening and standard cytogenetic analysis) allows us to increase the range of detectable CAs determined prenatally.

Genetic data plays an increasingly important role in modern medicine. Decrease in the cost of sequencing with subsequent increase in imputation accuracy, and the accumulation of large amounts of high-quality genetic data enable the creation of polygenic risk scores (PRSs) to perform genotype-phenotype associations. The accuracy of phenotype prediction primarily depends on the overall trait heritability, Genome-wide association studies cohort size, and the similarity of genetic background between the base and the target cohort. Here we utilized 8,664 high coverage genomic samples collected across Russia by "Evogen ", a Russian biomedical company, to evaluate the predictive power of PRSs based on summary statistics established on cohorts of European ancestry for basic phenotypic traits, namely height and BMI. We have demonstrated that the PRSs calculated for selected traits in three distinct Russian populations, recapitulate the predictive power from the original studies. This is evidence that GWAS summary statistics calculated on cohorts of European ancestry are transferable onto at least some ethnic groups in Russia.

Background: Germinal pathogenic variants are the cause of the development of hereditary cancer syndromes (HCS). Various genetic tests are used for HCS detect, from the «frequent» mutations of one or several genes analysis to the full-length gene sequence, next-generation sequencing (NGS) based panel, whole exome (WES) or whole genome sequencing (WGS).There are some HCS cases with atypical clinical manifestations and the family history does not allow one to suspect a specific HCS and limit oneself to the study of only one or a few genes. Conducting research using NGS to assess the selected sample of cancer patient’s genetic characteristics has revealed atypical HCS cases.Aim: To present the WGS diagnosis results for two atypical hereditary tumor syndromes cases.Materials and methods: DNA isolation was performed using Qiagen DNA Isolation kit. WGS for all samples was performed at DNBSEQ-T7 (MGI) and DNBSEQ-G400 (MGI) sequencing platforms using PCR-free protocol with average sample coverage 30x. A standard bioinformatics analysis pipeline was implemented for all the samples data processing.Potential clinically relevant variants were validated using Sanger sequencing. For all patients was received signed a written consent.Results: In the first case report, a pathogenic variant in the TP53 gene was identified: c. 637C > T, p. Arg213Ter, rs397516436, and Li – Fraumeni syndrome was confirmed. In the second case, we detected two pathogenic variants carrier — BRCA2: c. 6644_6647del, p. Tyr2215SerfsTer13, rs80359616 and MSH2: c. 1906G > C, p. Ala636Pro, rs63750875 associated with hereditary breast and ovarian cancer and hereditary colorectal cancer (Lynch syndrome).Conclusion: NGS, including WGS makes it easier to identify all clinically significant germline variants associated with hereditary cancer syndromes in cancer patients, as well as to trace their segregation in relatives.

A description of a patient with a rare form of Camurati-Engelmann Disease (CED), also known as progressive diaphyseal dysplasia, manifested by gait disturbance, pain in the limbs and muscle weakness is presented. It is only ca. 300+ patients with this disease have been described worldwide to date. It was discovered in various ethnic groups regardless of gender. A clinical case observation of this disease with molecular genetic confirmation of the diagnosis is presented for the first time in a Russian language scientific periodical. Establishing an accurate diagnosis in the described observation became possible only thanks to the use of a modern molecular genetic method, Next-generation sequencing (NGS). The clinical case observed in the article showed non-specificity of symptoms in this disease. It would be impossible to establish an accurate diagnosis without the use of top notch, modern genetic technologies in this case. The absence of specific symptoms coupled with the late manifestation of the disease suggest that not all of the cases of this disease are detected and diagnosed.

Cowden syndrome is a rare disease characterized by multiple hamartomas and increased breast, thyroid, kidney and uterine neoplasm risk. The lifetime breast cancer risk for patients with Cowden syndrome is 85 %, with an average age of diagnosis between 38 and 46 years. The diagnostic criteria for Cowden syndrome have been established by the International Cowden Consortium (ICC) and the National Comprehensive Cancer Network (NCCN), and are regularly revised, but the diagnosis of Cowden syndrome remains difficult due to the variety of phenotypic and clinical features of the disease. At the same time, the genetic variants associated with Cowden syndrome analysis is not a standard for patients with breast cancer.Objective: To demonstrate the non‑BRCA hereditary breast cancer detection using whole genome sequencing on the Cowden syndrome clinical case example.Materials and methods: The article describes a clinical case of a 37‑year‑old female patient with breast cancer, normal intelligence and phenotype, structural abnormalities of the thyroid gland (multinodular goiter). Whole genome sequencing was used to identify clinically significant genetic variants associated with hereditary tumor syndromes.Clinical case: The article presents a brief literature review on the clinical presentation of Cowden syndrome and indications for its molecular diagnosis. Also, the presented clinical case describes patient R., 37 years old female with breast cancer, who underwent treatment in the City Clinical Oncological Hospital № 1 of the Moscow City Health Department in 2021. The patient was fully examined and enrolled in the whole genome sequencing project under the Order № 69 of Moscow Healthcare Department dated February 1, 2021 «Oncogenetic research organization in Moscow». The results revealed a pathogenic variant in the PTEN gene, previously associated with Cowden syndrome.Conclusion: The use of whole genome sequencing allows to identify hereditary tumor syndromes, the clinical manifestation of which may be breast cancer.

ЦЕЛЬ ИССЛЕДОВАНИЯ Проанализировать результаты пренатального скрининга с применением неинвазивного пренатального тестирования (НИПТ) в Москве за период с 01.04.20 по 30.09.20. Оценить преимущество использования НИПТ перед комбинированным пренатальным скринингом в первом триместре беременности. МАТЕРИАЛ И МЕТОДЫ Проанализирован 5181 образец крови в период с 01.04.20 по 30.09.20. Неинвазивное пренатальное тестирование осуществляли методом полногеномного секвенирования. Для дальнейшего генетического исследования материала плода после инвазивных процедур проводили кариотипирование и молекулярно-генетический анализ. Для оценки эффективности сравнивали результаты, полученные при НИПТ, с результатами инвазивной пренатальной диагностики у пациенток в группе высокого риска и в группе риска 1:101—1:2500. РЕЗУЛЬТАТЫ Высокий риск хромосомных аномалий плода в отношении частых анеуплоидий по результатам НИПТ определен в 72 случаях из 5181:50 случаев трисомии 21, 17 случаев трисомии 18 и 5 случаев трисомии 13. Отмечено, что на уровень фетальной фракции влияют масса тела, индекс массы тела пациенток, наличие трисомий, пол плода. ВЫВОДЫ По предварительным данным, внедрение неинвазивного пренатального тестирования в практическое здравоохранение может снизить число ложноотрицательных случаев хромосомной патологии плода в группе риска 1:101—1:2500, а также потенциально уменьшить число инвазивных вмешательств в группе высокого риска. Вместе с тем в связи с небольшим размером выборки требуются дальнейшие исследования.

ЦЕЛЬ ИССЛЕДОВАНИЯ Проанализировать этические и клинические аспекты выявления случайных находок при использовании полногеномного неинвазивного пренатального теста. МАТЕРИАЛ И МЕТОДЫ С помощью полногеномного неинвазивного пренатального теста (НИПТ) проанализирован 5181 образец крови в период с 01.04.20 по 30.09.20. Для дальнейшей верификации результатов НИПТ проводили инвазивную диагностику с последующим кариотипированием и молекулярно-генетическим анализом. РЕЗУЛЬТАТЫ В 21 случае выявлен высокий риск редких трисомий по аутосомам и риск клинически значимых микрохромосомных аномалий плода или вариаций числа копий генов (copy number variation — CNV). ЗАКЛЮЧЕНИЕ Случайные находки при применении полногеномного НИПТ могут повысить эффективность пренатальной диагностики, позволив выявить редкие трисомии и микрохромосомные аномалии. Требуются дополнительные исследования для составления отечественных рекомендаций по выдаче случайных находок, выявленных пренатально с учетом клинических и этических аспектов.

Non-invasive prenatal testinging (NIPT) is a relatively new method aimed at detecting fetal chromosomal aneuploidies by analyzing extracellular fetoplacental DNA in the blood of a pregnant woman. NIPT has high sensitivity and specificity, and many professional communities now recommend its use as a screening method. Since its introduction into clinical practice in Hong Kong in 2011, NIPT has expanded rapidly around the world. The experience of various countries in organizing non-invasive prenatal testing is described in this article. Key words: NIPT, non-invasive prenatal testing, extracellular fetoplacental DNA, prenatal screening, prenatal diagnosis, invasive prenatal diagnosis, aneuploidy

Congenital malformations, chromosomal and monogenic disease play a significant role in perinatal mortality and child disability. According to the early prenatal screening results in the Russian Federation in 2018, the overall ratio of chromosomal anomaly prevalence is 1:250–1:300. Currently aneuploidy risk is calculated by using indirect biochemical and ultrasound markers, that have low sensitivity and specificity which can cause false positives and false negative results leading to unreasonable invasive procedures or missing chromosomal anomalies. It is well known that cell-free fetal DNA is detected in maternal blood. Whole‐genome sequencing based non-invasive prenatal testing (NIPT) can detect fetal chromosomal aneuploidy with high sensitivity as early as 10 weeks into pregnancy. The accuracy of determining fetal sex is also high: sensitivity and specificity are 98,9% and 99,9% respectively. Implementing molecular technology into clinical practice is required to improve prenatal diagnosis in the Russian Federation, icluding Moscow. Integration of NIPT to analyse cell-free fetal DNA will increase the efficiency of fetal chromosomal anomalies’ detection. However, there are some legal and ethical aspects to consider when integrating a new technology for wide-spread use. This review reveals arguable issues of NIPT integration into widespread clinical practice and possible ways of solving those issues. Key words: NIPT, noninvasive prenatal test, prenatal screening, fetal sex, invasive prenatal diagnosis, X-linked disease, chromosomal anomaly, chromosomal microarray analysis

The majority of research in the biomedical sciences is carried out with the highest resolution accessible to the scientist, but, in the clinic, cost constraints necessitate the use of low-resolution devices. Here, we compare high- and low-resolution direct mass spectrometry profiling data and propose a simple pre-processing technique that makes high-resolution data suitable for the development of classification and regression techniques applicable to low-resolution data, while retaining high accuracy of analysis. This work demonstrates an approach to de-noising spectra to make the same representation for both high- and low-resolution spectra. This approach uses noise threshold detection based on the Tversky index, which compares spectra with different resolutions, and minimizes the percentage of resolution-specific peaks. The presented method provides an avenue for the development of analytical algorithms using high-resolution mass spectrometry data, while applying these algorithms in the clinic using low-resolution mass spectrometers.