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0УДК 61 Adilova Sh.B., Beisenova A.Zh.
Adilova Sh.B.
student, International Medical Faculty, Asfendiyarov Kazakh National Medical University (Almaty, Kazakhstan)
Beisenova A.Zh.
Candidate of Biological Sciences, Associate Professor,
Department of Molecular Biology and Medical Genetics Asfendiyarov Kazakh National Medical University (Almaty, Kazakhstan)
SCIENTIFIC LITERARY REVIEW OF GENETIC BASIS OF AUTISM: DESCRIPTION OF NEW STATISTICAL DATA AND METHODS OF RESEARCH
Аннотация: autism spectrum disorders diagnosed in children of different ages are one of the leading problems of modern society. Autistic disorder is at the most severe end of a group of neurodevelopmental disorders called autism spectrum disorders (ASD). Modern scientists have developed methods for recognizing a group of genes and their groups leading to the development of ASD, but there is no specific autism gene as such. The NRXN family consists of three genes: NRXN1, NRXN2 and NRXN3. A small number of copies of NRXN genes or point mutations in them can cause the appearance of ASD. The NLGNfamily consists of five genes that encode neuroligins. The cause of ASD may be deletions or mutations of the NLGN4 gene reading frame shift. And this is only a small part of the genes that cause autism in a child in premutation of their combinations. Based on these studies, the latest methods of early diagnosis of autism or predisposition to it in the embryonic period of fetal development and ways to identify a complete list of mutations caused by specific types are being developed.
Ключевые слова: autism, ASD, genes, locus, premutation, genetic test.
April 2 is celebrated annually as World Autism Awareness Day. It was established by a resolution of the UN General Assembly on December 18, 2007, which expressed concern about the high number of children suffering from autism. According to the World Health Organization, 1 in 160 children suffers from autism spectrum disorder (ASD). [3]
Autism disorder falls on the more severe end of a group of neurodevelopmental disorders called autism spectrum disorders (ASD). A meta-analysis of the prevalence of ASD shows that it affects approximately 37 people in 10,000. ASD covers several clinically defined conditions: pervasive developmental disorder unspecified and autistic disorder are the most common, while Asperger's syndrome is less common. The risk of ASD is increased in boys, an effect that becomes even more pronounced in so-called high-functioning cases. [1]
Autism is a complex, disintegrative disorder of mental development characterized by severe, pervasive deficits in social interaction and communication, as well as restricted interests and repetitive patterns of behavior. The disease was first described in 1943 by L. Kanner. The broad autism phenotype also applies to people with some symptoms of autism who do not meet all the criteria for autism or other disorders. [3] The American human rights organization Autism Speaks is considered one of the largest in the world, specializing in studying this disease, informing society about how to treat it and how to help people with autism.
One of the latest studies, organized by volunteers of the Autism Speaks project, allowed scientists to identify 18 new mutations and variations of genes that increase the risk of autism. The researchers also noted that many of the 18 newly identified autism genes affect the functioning of certain biological processes in the brain. These processes, in turn, have an effect on the development of neurons and the way they communicate impulses with each other.
"Of the 61 types of gene mutations we have discovered, 80% have an effect on biochemical processes in the brain," explains Dr. Pletcher. "This sets a clear goal for the medicine of the future to stop this kind of process."
The research data was presented to experts in the journal Nature Neuroscience. As part of it, scientists analyzed 5205 genes from representatives of families in which cases of autism were recorded. To date, this study is one of the largest of its kind. [2] There is still no single etiological concept of ASD. Previously, some researchers described autism as an organic pathology, others noted as the cause of the development of ASD: a violation of the adaptive mechanisms of an immature personality, special constitutional condition, schizophrenic post-attack state, condition with fragile X chromosome syndrome. Heavy metals, infectious diseases, vaccines, food, alcohol, maternal stress during pregnancy, and even diesel engine exhaust have been studied as environmental factors in the development of ASD. In this regard, the term "atypical" or "syndromic" autism is currently accepted - autism, which is one of the symptoms of another disease. Genetic and chromosomal causes account for 2550% of autism cases. [4]
Scientists S. Folstein and M. Rutter reported that there was not a single case of an autistic child with an obviously autistic parent, however, they noted that autistic people rarely marry and rarely give birth. True, this was in 1977, it is possible that such cases were subsequently documented, but we were unable to find them. They also conducted a study of 21 same-sex twin pairs, 11 monozygotic (MZ) and 10 dizygotic (DZ). As a result, S. Folstein and M. Rutter found 36% concordance among monozygotic twins and no concordance among dizygotic twins. For a long time, it was this research that determined ideas about the genetic nature of autism.
These results were later confirmed in 27 same-sex pairs of monozygotic twins and 20 pairs of dizygotic twins in a study led by E. Bailey in 1995. The scientists found that 60% of monozygotic couples were concordant for autism, among dizygotic couples, concordance was 0%. High concordance in monozygotic twins indicated a high degree of genetic influence. Nonconcordant monozygotic pairs had a significantly higher incidence of obstetric complications, which the authors attributed to prenatal developmental anomalies, as evidenced by the very high incidence of minor congenital anomalies in the affected twins. Scientists have also reported an association of autism with increased head circumference. [3]
Today it has been proven that a number of genetic conditions are indeed associated with autism. ASD affects 25-47% of patients with fragile X syndrome, 510% of patients with Down syndrome. Autism is also characteristic of Engelman, Joubert, Cohen syndromes, epileptic encephalopathies and other syndromes. Autism is a complex, multifactorial disorder involving many genes. To date, several loci have been identified, some of which may cause the autistic phenotype. For example, AUTS1, which was mapped to chromosome 7q22. However, the genetic basis of idiopathic autism appears complex. Most likely, the condition is based on several loci, and environmental factors, although not a key influence on the development of ASD, can act as an additional "blow" for people genetically prone to autism.
The "autism gene" does not exist, despite the occasional loud headlines in the media. But the list of genes that may be associated with autism is growing. According to 2017 data, 65 genes were found that are strongly associated with autism, and more than 200 genes that have a weaker relationship. [3]
FX syndrome refers to the so-called inherited syndromes (Fig. 1). This means that the birth of a child with FX syndrome is caused by the presence of a mutation in the corresponding gene in the child's mother (the FMR1 gene on the X chromosome). A gene mutation manifests itself in an increase in the number of so-called CGG repeats. It is also important to understand that due to the presence of a second, "healthy" X chromosome in women, even in the case of a complete mutation (the number of CGG repeats is more than 200), symptoms of the disease may not be expressed. Therefore, very often a woman is not aware of the presence of a health problem until the moment when the correct diagnosis is made to one of the family members. So, a mother who is a carrier of a complete mutation of the FMR1 gene has a 50% probability of passing on a mutant X chromosome to her child. If a boy is born into a family, then he will already have all the signs of FX syndrome. If it is a girl, then the violations may again remain barely noticeable and not go beyond the difficulties of schooling. [6]
Fig. 1. Model of spreading of the mutant X - chromosome associated gene.
If the child's mother has a premutation of the FMR1 gene (the number of repeats from 50 to 200), then in the next generation there is usually an increase in the number of repeats, which can either reach the stage of a complete mutation or remain at the premutation level. In this case, the risk of having a sick child in subsequent generations remains.
The risk of developing FX syndrome in a child depending on the number of CGG repeats in the mother (Sarah L. Nolin, et. al. Am J Hum Genet. Feb 2003).
Fig. 2. Correlation of quantity of premutations in mother's organism to possibility of development of risks of CGG - repeatings in child's organism.
If the father has a premutation, inheritance of the disease is also possible. However, when a mutant X chromosome is inherited from a man, there is no increase in the number of CGG repeats. Therefore, there is only a risk of having a girl with a premutation. The possibility of giving birth to children with a full mutation remains in subsequent generations. [6]
The NRXN family consists of three genes: NRXN1, NRXN2 and NRXN3. These genes encode neurexins (NRXN), adhesion proteins that are located on the presynaptic membrane and bind to their postsynaptic counterparts, neuroligins. A low copy number of NRXN genes or point mutations in them can cause ASD. The NLGN family consists of five genes that encode neuroligins. ASD may be caused by deletions or frameshift mutations in the NLGN4 gene. As a result, the synthesized protein is shorter than necessary to fully perform its functions. There are also cases of point mutations in the NLGN3 gene, which presumably lead to the appearance of ASD[9]. The SHANK1, SHANK2, SHANK3 genes encode phosphoproteins of the same name. All of them are ASD-associated, but the SHANK3 gene has the greatest diagnostic significance. It encodes a protein that is necessary for the formation of neural connections. With a lack of SHANK3 protein, the function of NMDA receptors (n-
methyl, D-aspartate), which play an important role in the regulation of higher nervous activity, is impaired [10].
The scientists found that 15 of 6,176 children with ASD had a mutation in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8), and all of these cases had similar characteristic physical signs and problems with sleep disturbances and gastrointestinal diseases. A total of 15 independent mutations were identified, and no truncation events were found in 8792 control subjects, including 2289 unaffected siblings. In addition to the high likelihood of an ASD diagnosis among patients carrying the CHD8 mutation, macrocephaly, distinctive facial features, and gastrointestinal disorders have been added to the characteristics expanding this group. Raphael Bernier, PhD, lecturer in psychiatry and lead author of the study, said: "We have finally identified a specific gene as the exact cause of autism. This will be a dramatic change in the way autism is studied. Although this type of autism, associated with the CHD8 mutation, will be seen in less than half a percent of all children, this study is significant." The study was published on July 3, 2014 in the journal Cell [13].
The genes described above are only a small part of those that may be associated with autism spectrum disorders. Given the amount of research on ASD, this list will grow in the coming years.
"Autism is a genetic disorder. If a child with autism is born in a family, then the risk that the next child will also have autism is about 20 percent," a candidate of psychological sciences, a leading researcher at the Moscow State Psychological and Pedagogical University, told RG. researcher at the University of Gothenburg Elena Orekhova.
"The age of the parents plays a role here, especially fathers," Elena Orekhova clarifies. "If the father is over 55 years old, then the risk of autism in the child is much higher than if the father is under 30. And the age of the mother matters less." Interestingly, autism is more common in boys than girls. Similar changes in genes are more likely to lead to autism in boys than in girls [14].
Controversial issues in diagnosing autism spectrum disorders come down to several main aspects:
• lack of a unified diagnostic method,
• diversity of approaches to understanding the essence of autism spectrum disorders,
• ambiguity in the interpretation of the terms "autism" and "ASD",
• vagueness of diagnostic criteria.
All this leads, on the one hand, to a significant number of people with undiagnosed autism spectrum disorders, and on the other hand, to overdiagnosis of ASD in some regions. [7]
Genetic tests for people with autism are still not a medical standard, and they are often inconclusive, but sometimes the information they provide can be life-changing. Consider the example of James, when James was born in April 2003, it was obvious that he had problems. He failed a newborn screening test and had difficulty breathing, so he was sent straight from the delivery room to the neonatal intensive care unit. Doctors suspected he had a genetic disorder, but genetic testing, which was adopted 15 years ago, did not provide any answers. A genetic test that was not available when James was born later showed that he had a mutation in a gene called TAF1. This mutation likely led to autism, intellectual retardation, and several other problems.
Genetic tests cannot be used to diagnose autism. There are no known mutations that lead to autism 100% of the time. However, as happened in James' case, the results of genetic testing can influence the approach to treatment or prevention. Some mutations are associated with an increased risk of various medical problems, such as epilepsy, obesity or kidney failure. Information about them also helps bring people with a common mutation together - in some cases, families of such people have come together, shared information about common features, and even initiated new research into the condition. In addition, knowledge of the specific risks associated with the mutation helps families make decisions about having other children.
A survey of 108 pediatricians in the US state of Utah found that 70% of them had never prescribed genetic testing for autism, or did so only after the recommendation of another specialist. "During my training and practice, I had never been told about anything like this," says Paul Carbone, a pediatrician and lead
researcher at the University of Utah who is directing James' medical care. "This is an ever-evolving and complex field, and it takes a real effort to stay up to date with the latest information."
A standard microarray test could have saved Calleen Kenney years of worry and guilt, but when her daughter Maya was born 20 years ago, it wasn't available. When Maya was 2 years old, doctors tested her for several genetic syndromes that can lead to autism, including fragile X syndrome and Angelman syndrome. Maya had a chromosomal microarray test and Kenney learned that her daughter was missing a genetic region called 22q13, resulting in Phelan-McDermid syndrome. The syndrome, which can lead to autism, also affects the kidneys and eyes, and Kenney immediately thought of Maya's ongoing problems with urination and blocked tear ducts. Since then, Maya has undergone regular check-ups for her kidneys and eyes.
Maya syndrome is one of the few causes of autism that are associated with large chromosomal mutations. In many other cases, the mutation affects only one gene—and recent estimates suggest there may be hundreds of such genes.
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Fig. 3. Results of a study of genes associated with ASD [8].
Exome sequencing is the only way scientists can compile a complete list of mutations associated with autism (Figure 3). For this purpose, John Constantino's team offers exome sequencing to anyone who comes to their autism clinic at Washington
University in St. Louis, USA. The team first conducts microarray analysis and then prepares the case for exome sequencing for the insurance company.[5]
One hundred and two genes with their complex interactions are enough to provide work for a large number of researchers. But the situation becomes even more complicated if you read the publication of Jian Zhou and his colleagues, who state that the formation of autism can be influenced not only by exons, but also by introns of the genome [11]. This turn forces us to look at the problem of diagnosing ASD from an unexpected angle and poses new challenges for researchers.
It is important to note that despite the considerable attention that researchers have devoted to studying the genetic markers of ASD, there is no clear direct link between autism spectrum disorders and a specific mutation. Today we can only say that there are genes that increase the risk of autism spectrum disorders [12].
СПИСОК ЛИТЕРАТУРЫ:
1. Текст составлен по материалам статьи Бретта С. Абрахамса и Даниэля Х. Гешвинда «Advances in autism genetics: on the threshold of a new neurobiology» (см. также иллюстрацию к ней «FIGURE 1 | Loci implicated in ASD etiology»). Онлайн-версия расположена по адресу http://www.aspergers.ru/node/175;
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13. University of Washington// Illumina// Agilent;
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