Research Centre for Medical Genetics
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International Day of People with Down Syndrome

March 21 is the International Day of People with Down syndrome. This is the most frequent, well-studied syndrome, the diagnosis of which does not pose any challenges.

FSBI Research Centre for Medical Genetics, an organization subordinated to the Ministry of Science and Higher Education, is the leading medical genetic institution in Russia, the head organization of the entire national medical genetic service. RCMG ranks first in Europe by a number of diagnosed hereditary diseases

Today, RCMG is the only federal institution in Russia that effectively combines research work and medical activity. The Center studies the etiology and pathogenesis, that is, the causes and mechanisms of hereditary diseases, develops and introduces new technologies for diagnosis and treatment methods thereof. In 2018, the Centre physicians accepted 12 thousand 169 families, i.e. 27 thousand 150 people. They carried 45,104 high-tech genetic studies, including 11,000 as part of the state target. This means that the studies were free for patients. RCMG is the only medical institution in Russia that has performed so many genetic studies.

Among the RCMG patients, there are those who seek an advice for Down syndrome. Doctors of the Centre provide highly qualified assistance.

Down syndrome (DS) is caused by the presence of three copies (trisomy) of the 21st chromosome. The syndrome is diagnosed based on the identification of characteristic external features (phenotype), and is confirmed by the study of the karyotype (analysis of chromosomes in the microscope).

DS is characterized by physical and mental-and-speech developmental delay in combination with a high incidence of congenital disorders, including heart, gastrointestinal tract, as well as an increased risk of diseases associated with the syndrome, such as hypothyroidism, celiac disease, and many others. However, it does not mean that the whole range of associated diseases will develop in every child with DS.

According to Natalia Semyonova, Candidate of medical science, senior researcher of the Research and Counselling Department, geneticist of the highest category: “As provided by the literature, in 95% of cases the Down syndrome is a result of complete trisomy of the 21st chromosome that occurred due to chromosomes nondisjunction during the formation of reproductive cells in one of parents. That is, there are three copies of the 21st chromosome in each cell instead of two. The remaining 5% of cases occur in translocation forms. This is a complex interchromosomal rearrangement, in which an additional material of the 21st chromosome is obtained and mosaicism occurs: only some of the cells of the body contain the additional 21st chromosome, the other cells have a normal chromosomal set. In the case of translocation form of DS, it is necessary to examine the parents, since one of them may be a carrier of balanced chromosomal rearrangement with an increased risk of having a child with chromosomal syndrome. Thus, chromosomal abnormality occurs even before conception, and this circumstance often surprises parents, linking the onset of the syndrome with severe pregnancy, stress, and taking various medications during pregnancy. According to the literature, chromosomal pathology occurs in approximately 1% of healthy parents.

The global average distribution of DS is 1: 1000 live births. No racial and socio-economic supplies determine the probability of having a child with DS, it largely depends on the mother’s age. For example, the risk of having a child with trisomy of the 21st chromosome in a mother aged 30 will be 1: 1000, and in a mother aged 40 - 9: 1000.

The prevalence of DS depends to some extent on the traditional and religious characteristics of the region. In countries where abortion is not accepted, prevalence is higher.

Pursuant to the Russian Federation Ministry of Health Order No. 457 of December 28, 2000, “On improving prenatal diagnosis in the prevention of hereditary and congenital diseases in children”, in Russia, as in many other countries, antenatal DS screening is carried out to all pregnant women, regardless of their age. Screening of the first trimester (made at 11-13 weeks) includes a search for markers of chromosomal abnormalities in the fetus by ultrasound examination (thickness of the collar space, size of the nasal bone, etc.) and biochemical analysis of the mother’s blood (the level of certain indicators is assessed). The results of both studies carried out simultaneously are analyzed using computer programs. If a pregnant woman is at high risk (the probability of having a child with DS is higher than 1 in 100), you need to gain a clear understanding that this is not a diagnosis. This is only a selection of high-risk groups. As with any screening method, both “false-positive” and “false-negative” results are possible. In such cases, the geneticist further advises the expectant mother, explains in detail the results of the screen, and offers an additional research on the karyotype of the fetus by invasion (chorionic biopsy, amniocentesis, cordocentesis). An invasive study certainly has the risk of complications, but these complications are quite rare (about 1%).

Another most effective screening method is the non-invasive prenatal test (NIPT). Its effectiveness reaches 97-99%. Multiple pregnancies show the invalid results, as well as mosaic and translocation forms of DS. The essence of the method lies in the study of fetal DNA isolated from the mother’s blood. The analysis is possible since 9 weeks’ gestation period and is financed by the family.

It is necessary to remember that NIPT is also a screening method that needs to be confirmed - fetal karyotyping.

If DS is detected in the fetus during pregnancy, up to a certain period, it is possible to terminate such a pregnancy. In any case, ONLY the family decides whether to terminate or maintain a pregnancy. Our experience suggests that most mothers prefer abortion in the event of the fetus disease, but some families choose to have a sick child. Parents should clearly understand what difficulties they could expect with the birth of a child with DS, and the geneticist should be as objective as possible, but not prescriptive, to bring all the necessary information to the parents in order to ensure that the family can make an informed decision.

The use of prenatal screening should have an impact on the prevalence of DS in the population. However, the UK’s studies (2011) that analyzed the twenty-year application of prenatal DS screening programs with the analysis of the biochemical parameters level in maternal blood in combination with ultrasound examination of the fetus, concluded that the prevalence of DS among live births, in general, had not changed. An increase in maternal age, on the one hand, and an increase in the survival rate of children with 21ST chromosome trisomy, on the other hand, produced a compensating effect of prenatal diagnosis.

The improvement of medical care for children in recent decades has led to a significant decrease in infant mortality and an increase in the life expectancy of patients with DS, mainly due to the successful surgical correction of congenital heart defects and gastrointestinal tract. The life expectancy of people with DS in recent years has increased significantly, as well. Thus, in the United States, it was 25 years in 1983, and it was 49 years already in 1997.

Specialized medical preventive guidelines and recommendations significantly contributed to the improvement of the quality of life and social adaptation of people with DS. The use of preventive observation recommendations allows you to diagnose diseases associated with the syndrome before the development of irreversible effects, to carry out prevention and treatment of these diseases in children with DS, as well as to prevent the occurrence of a secondary developmental delay due to a concomitant pathology.

The development of molecular genetics made it possible to have a more detailed understanding of mechanism of the syndrome symptoms formation. Despite the fact that the DNA detailed analysis is still ongoing, areas (critical regions) responsible for the development of DS most symptoms were identified. The pathogenesis (mechanism) of formation of patterns and associated with the syndrome of the disease manifestations relates to the "dose-effect" of genes located on the long arm of the 21st chromosome. For example, the gene of type 6 collagen is associated with the development of muscular hypotension and increased mobility of joints in DS. The superoxide dismutase 1 gene is “responsible” for the development of premature cell aging and Alzheimer's disease in DS patients. Therefore, scientists have turned their attention to the development of methods that enable the "off" extra genes of the 21st chromosome, having received new approaches in gene therapy. However, today it is only a research. There is no special etiological treatment for DS patients.”

Discussion of genomic editing technologies has long gone beyond a limited group of specialists. Increasingly, they say that this method will allow treating not only hereditary pathology. Can we call it a panacea? Experts will explain.

Svetlana Smirnikhina, Candidate of medical science, and Head of the Genome Editing Laboratory, RCMG: “Genome editing has recently become such a popular topic that many people take this technology as a panacea. This is not the case. First, genome editing is effective only for treating the diseases caused by mutations in the genome, leading to the disease in 100% of cases. In the case of multifactorial diseases, this technology is powerless. Second, the formation of the extra 21ST chromosome leads to the development of Down syndrome but not the usual genetic “breakdown” (mutation). 47 chromosomes, but no 46, represent the karyotype of such patients. We certainly are making serious progress in genomic editing. CRISPR \ Cas9 technology should allow cutting the damaged sections out of the DNA chain and replacing them with intact ones. We are one-step closer to success at least in relation to one gene, CFTR. However, it is impossible to cut out a whole chromosome that contains thousands of genes with the help of these “scissors”.

The development of technologies allows us to increase the accuracy of DS diagnosis every year, but the science is not yet able to offer effective methods for its prevention and treatment. All that specialists can do is to identify the pathology in a timely manner and provide parents with comprehensive information.