REGISTRO DOI: 10.5281/zenodo.10269678
Samara Oliveira Santos
Thaylana Cleide Moreira Carvalho
Orientadora: Marisa Salvi
Orientador: Marcus Vinicius Cardoso Matos Silva
ABSTRACT
The following work sought to describe, investigate and evaluate polymorphic changes in the ADNP, CHD8 and SHANK3 genes, in their demonstration with Autism Spectrum Disorder (ASD), with Autism Spectrum Disorder being a set of disorders that directly affect the individual at the level neuropsychic, causing damage to communication, social relationships, motor difficulties, among others. Polymorphism is a genetic change that can lead to pathologies. In addition to studies with gene polymorphisms, a common frequency was noted in patients with ASD, thus helping in the diagnosis of this disorder, not being identified early and useful in the better development of Autism. An integrative literature review was carried out, with a descriptive, explanatory character, according to a qualitative approach on the types of polymorphic genes and their association with the Disorder.
Keywords: Polymorphism. SHANK3. ADNP.CHD8. AUTISM.TEA.
1. INTRODUCION
Studies on neurodevelopmental disorders are increasing in prevalence; more patients are being diagnosed with neurological problems, which cause impairment in communication skills, intellectual skills, interaction, behavior, among others. Examples of neuropsychic problems include intellectual development disorder, communication disorder, attention deficit/hyperactivity disorder, specific learning disorder, motor disorder and autism spectrum disorder (DIAGNOSTIC AND STATISTICAL MANUAL OF MIND DISORDERS: DSM-5,
2014).
Being a neurodevelopmental disorder, autism spectrum disorder is described by deficits in communication; difficulties in social relationships; stereotyped behavior; restricted interests and standardization of activities. Its incidence is growing, data shows that 1 in 88 people is autistic, according to the CDC, in Brazil the number of autistic people reaches 2 million and worldwide the estimate is 160:1 children; other research states that by 2050 the number of autistic people will increase by 42% (RIBEIRO, 2018; ALMEIDA; NEVES, 2020; COSTA, 2020). By linguistic definition, the word “polymorphism” (from the Latin “polymorphism”) means many (poly) forms (morph), i.e. various forms of something or parts; it refers to gene alterations, which include, exclude or vary nitrogenous bases, leading to changes in metabolic functions, such as enzymatic actions or protein synthesis in the body, with genetic, environmental, exposure, nutritional and drug influences (PESSOA, 2022).
According to evaluations, genes are directly involved in the risk factors for autistic children. Through syndromic forms, we can observe genetic morphologies that are associated with ASD in complex conditions. According to a study carried out at the Medical Genetics department in Buenos Aires, it is possible to recognize copy number variants (CNV) and single nucleotide polymorphisms (SNP) in localized regions of the genome, which can have variable phenotypes, but are not necessarily specific, finding results in up to 17% of cases. Based on this research, the correlations of ADNP, SHANK3 and CHD8 polymorphisms that may be associated with Autism Spectrum Disorder are evident (ARBERAS; RUGGIERI, 2019).
Data shows an estimated 2.2% recurrence of the disorder when one of the children already has autism, with a population prevalence of 10 or 13 in 10,000 individuals. In addition, there are more current statistics that show that every 88 individuals have the disorder, so the need for early diagnosis is notorious; because the faster the diagnosis, the more agile the multidisciplinary treatment will be, which will influence the improvement of development through therapeutic measures and the use of appropriate medications for related comorbidities (Costa, 2018).
Our aim is to analyze the influence of polymorphic markers in the ADNP, SHANK3 and CHD8 genes on Autism Spectrum Disorder (ASD), investigating the frequency of polymorphism in the ADNP, SHANK3 and CHD8 genes associated with autism and analyzing the relationship of genetic alteration with the ADNP, SHANK3 and CHD8 polymorphisms.
2. METHODOLOGY
This is an integrative literature review with an explanatory descriptive approach, being a research aimed at locating studies that reported some existing knowledge, with a qualitative approach, with the purpose of citing some types of polymorphisms that may be associated with Autism Spectrum Disorder (LAKATOS, ET AL, SÃO PAULO, 2013).
To do this, scientific articles were used from the following databases: Scientific Electronic Library Online (sciELO), Latin American Literature in Health Sciences (LILACS), National Center for Biotechnology Information (in Portuguese PUBMED), using the following key words: autistic disorder, genetic polymorphism, autistic spectrum disorder, modifier genes, as well as the Boolean operator, searched in three languages: Portuguese, English and Spanish.
Other connectors used were: and; y.
The articles were screened using Bardin’s methodology. For the inclusion criteria, articles were selected between 2013 and 2023, which contained as a theme the polymorphic genes SHANK3; ADNP; CHD8; with a focus on autism. the separation of articles took place through Boolean research that used the auxiliary connectors in the search for articles and research related to the following theme. The exclusion criteria were articles that did not fit the inclusion criteria, as well as articles that deviated from the proposed theme.
3. RESULTS AND DISCUSSIONS
In order to systematically understand the results, those articles were analyzed which would answer the subject’s objections. According to the data obtained, this influence of genes, called polymorphisms, on Autism Spectrum Disorder will modify the genes through exposure, where they will be expressed in various ways; at the neural level it happens according to the types of polymorphism, which can be deletion; insertion or variation, varying in degrees and causing the actions and functions of the organism affecting mainly the communicative, motor, cerebral and other functions of the individual; being able to correlate more than one disorder.
The ADNP, SHANK3 and CHD8 genes are linked to the influence of autism because they will behave in the individual’s organism and will help in the testing and observation of their performance, which will function as regulators and protectors, remodeling the cell and helping in the correct expression of genes, as well as being signposts that will be present in synaptic actions.
According to Pessoa, NYEDJA, 2022, the CHD8 gene (Chromodomain Helicase DNABinding Protein 8) is of paramount importance in the association with ASD, as it is a remodeling and compaction gene responsible for influencing gene transcription, acting on the command of neurons and their size; in another article, studies suggest that CHD8 represses Wnt/βcatenin target genes and p53-dependent apoptosis, ensuring a loss of function of the gene by interrupting its expression, thus affirming its relevance in the etiology of ASD. The gene directly regulates human neurodevelopment, which if there is a loss of its regulatory action will imply the normal proliferation and differentiation of neuronal progenitors, due to its absence. The action of conversions between the binding sites of this gene, show a link to the risk of developing autism, related to the number and its gene deregulation (COTNEY et al., 2015); mutations in the CHD8 gene have been observed in less than 0.5% of cases, making it a gene that has higher prevalence ratios than other previously associated genes; there are more than 30 mutations of this gene in people with ASD (GHR, 2017).
SHANK3 is a member of the SHANK 1- 2 -3 family, which is of great importance because it acts in the cerebral cortex and cerebellum by encoding a structural protein, a signaling complex linked to the cytoskeleton of the postsynaptic density of most excitatory glutamatergic synapses in the human brain; acting to support synaptic connections between neurons (PESSOA, 2022; JIANG; EHLERS, 2013). SHANK 3 can vary its alterations in several ways, being related to other problems such as the maturation and formation of dendritic spines, responsible for the transmission of nerve impulses, occurring when this protein is altered or deleted; also associated with Asperge syndrome / and ASD when related to the number of extra copies of the protein (FRECHE et al., 2012; GONG et al., 2012); The deletion of SHANK 3 also implies the development of Phelan-McDermid syndrome, with clinical aspects related to ASD such as: absence or delay of speech, hypotonia, intellectual disorders, among others (RIBEIRO, 2018).
In studies carried out to verify alterations in SHANK3 in rats, compulsive and repetitive behaviors were observed, as well as difficulties in social interaction, which are the main symptoms of ASD. Biochemical, morphological and electrophysiological analyzes revealed synaptic dysfunction in corticospinal synapses, which are part of the neural circuit affected in ASD (RIBEIRO, 2018; PEÇA et al., 2011); Its haploinsufficiency caused a monogenic form of autism, which can be taken into account in laboratory tests according to its frequency, thus serving as a possible aid in diagnosis (ROSAN, 2015). There are around 43 mutations in the SHANK3 gene found in people with autism spectrum disorder; they are frequent in 2.12% of cases (ROSAN, 2015).
The ADNP gene (activity-dependent neuroprotective protein) is a neuroprotective protein that is essential for the development of the human brain, acting to instruct the synthesis of a protein responsible for chromatin remodeling, thus influencing the activity of genes. In the remodeling process, this gene binds to DNA that will interact with SWI/SNF protein complexes that will direct changes in chromatin structure. Individuals who have mutations in this gene are associated with ASD as well as its syndrome, who will have more severe intellectual disabilities; they will also have symptoms and signs such as: food restriction since childhood, hypotonia, attention deficit/hyperactivity disorder, obsessive compulsive behavior, etc. Mutations of this gene will also present dysmorphic features including a prominent forehead, eversion of the eyelid, a wide nasal bridge, a high hairline, a thin upper lip and a smooth medial cleft (RIBEIRO, 2018).
4. CONCLUSION
After reading the articles and formulating the results, we concluded that the SHANK3, ADNP and CHD8 genes are related to Autism Spectrum Disorder because their alterations directly affect brain function and development, thus contributing to the onset of the disorder. There is no curative measure for ASD, only prophylactic measures which will help to reduce symptoms, requiring medical and other professional monitoring, as well as the use of medication in most cases. Since there are correlations between the development of the disorder and polymorphic types due to their connection with the nervous system and the various alterations in these and other systems, there is a need for greater attention and a search for family members who have someone with ASD, as well as for professionals with more in-depth knowledge of the subject, which can help in the early identification or improvement of the quality of life of those individuals who have the disorder and discovered it late. The insertion and search for genetic tests will help to evaluate the alterations, thus verifying each alteration.
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Samara Oliveira Santos – Undergraduate student in BiomedicineInstitution: UNIFACS – University of Salvador Address: R. Rio Tinto, 152 – Santa Monica, Feira de Santana – BA E-mail: samaraoli578@gmail.com1
Thaylana Cleide Moreira Carvalho Undergraduate student in Biomedicine Institution: UNIFACS – University of Salvador Address: R. Rio Tinto, 152 – Santa Monica, Feira de Santana – BA E-mail: thaylanac.carvalho@gmail.com2