The Genetics of autism, a complex human disease - Dissertation Example

? "Genetics of Autism" Introduction Linkage Studies Content Autism Genetics Genetics and Controversy Ethical issues to use genetic markers for Autism Genome Wide Association Studies Chromosomal Abnormalities Submicroscopic copy number variation Genetic Mechanisms Involved in Functional Pathways Genetic Counselling Conclusion Literature Cited Abstract Autism is an intricate performance defined, stationary condition of undeveloped brain, which is emerging as a subject of great concern due to augmentation in number of cases with time. Pediatricians across the world find the prevalence of autism greater than other conditions such as spina bifida, and genetic anomaly, trisomy of 21st chromosome, the Down Syndrome. Autism is not a disease condition but it displays genetic and non-genetic basis. Autism encompasses a wide range of developmental disorders and therefore it is considered as the autistic spectrum disorders (ASDs) regarded as an extensive variety of behavioural provinces involving- lack of social interaction by the child; inappropriate language and communication skills; diminished activities. Research studies carried out for the past 5 decades now establish the fact that autism is the result of multiple interaction of genetic factors. Considering the epidemiology of autism, various environmental factors encompassing exposure to toxic chemicals such as teratogens which are responsible for causing developmental abnormalities, perinatal abuse, infections during prenatal phase involving rubella and cytomegalovirus, epilepsy are the most probable reasons that is known to be responsible for causing autism. Studies also reveal the association of autism with frequency 100 different genes are found to be associated with the autism (Herman, 2007). Genetics and Controversy In order to find out the causation of autism, individuals belonging to different domains are contributing their best to reach to a conclusion at the faster pace. Scientists are contributing through molecular and genetic analysis while physicians are involved in tracing out the prenatal as well as postnatal history, symptoms and behavioural pattern, families are highlighting the significance of disease in their own way depending upon their cultural predisposition. Thus autism is emerging as a matter of paramount significance as it involves individuals belonging to different disciplines. In certain cases media reported the disease as an implication of bad parenting, but now it has been established that autism has a biomedical origin. Concern about the autism and role of some environmental factors in it prevalence has raised apprehensions across the globe and families of autism cases want to rule out the reason for the condition of autism to prevent the future children from combating the condition. According to Persico & Bourgeron, (2006), numerous environmental factors are found to play significant role in the autism causation, these factors are found to be related with mercury in the environment, childhood vaccination where mercury was used as preservative. Some of the other contributing factors involves pollutants in the environment, prenatal stress, ultrasound waves, the radiation, precipitation as in an area and also from the television. Controversies are ubiquitous and research believes on the facts, it is therefore National Academy of Science's Institute of Medicine, has established the fact that autism is not related with the childhood vaccines (Verstaeten et al, 2003). Blaming parents and their defective genes for the child's autism may result in an emotional turmoil, a noteworthy segment of the genetic involvement to autism could be explained by CNV. The final agreement is of great connotation that autism is the result of an amalgamation of the genetic and environmental factors and genetic predicaments for autism cannot exclude environmental factors responsible for inducing autism. The deterioration of natural environment and augmentation in the number of autism cases co-exist and some relationship could be established (Rutter, Moffitt & Caspi, 2006). Further, it could be manifested that genetic population and gene frequencies have not been changed in the past couple of decades which is not comparable with the augmentation in the cases of autism. Moreover, environmental influences cannot be ignored totally. A need for higher resolution of the population and associated environmental predicaments must be assessed. Ethical issues to use genetic markers for Autism The use of genetic markers in the susceptible population to find out the potential of autism in the given set of conditions in a population highlight, laid the foundation of ethical, legal and social issues (Marchant & Robert, 2010). Genome wide association studies The genetic studies carried out for the candidate genes involve specific hypothesis. As the population is heterogeneous, bias may be presented by techniques involved and environmental factors in non-reproducibility of the results. Often false negative reports are generated which obstructs further understanding of genetic mechanism involved in autism. Genome wide association (GWA) studies have been carried out to eliminate the possibilities of false positive reports. The study involves large sample size and replication of most significant SNPs (Skol et al, 2006). However, GWA studies performed with the presently accessible samples and with the presently obtainable SNP assays are unable to identify risk alleles with potentially little insignificant allele incidence or infrequent deviations which could be or significance in understanding the aetiology of AD (McCarthy et al, 2008). It is established by two independent studies that common genetic variants on 5p14.1 and 5p15 could be replicated responsible for transporting a little augmented menace (OR 1.2) or protective effect (OR 0.6), while, 5p14.1 segments are evolutionary conserved sequences. Genes CDH9 and CDH10 are found to be present in the vicinity of the replicated SNPs and are responsible for coding cadherins, proteins concerned with calcium-dependent cell–cell junctions in the nervous system, thus they are responsible for determining structure as well as functional connections of the brain (Weiss, 2009). Chromosomal abnormalities Observation reveals that heterogeneity in AD is related with the chromosomal anomaly and this could be detected by means of karyotyping. Conditions of analysis could not be standardized which results in shortcomings in cytogenetic studies and lack of standardized assessment of cognitive and adaptive functioning (Freitag, 2010). According to Reddy (2005), 3-5% of the cytogenetic anomalies is reported in AD cases. While the analysis carried out by Freitag (2010), it could be understood that about 1%, of the prevalent cytogenetic abnormalities are pragmatic on chromosome 15q11-13, the prevalence of these anomalies is in majority of cases maternally, but paternally inherited duplications may persist. Further, findings related to the deletion of 2q37 and 7q31 on chromosomes 2 and 7 respectively or duplication of 22q13 may be attributed to the propensity of AD. Besides these, other X-chromosome related anomalies such as Klinefelter Syndrome (XXY), along with the Williams–Beuren–Syndrome where duplication of region 7q11.23 occurs and Velo-cardio-facial Syndrome where deletions of 22q11is reported; are found to be connected with the augmented autism. Traits of autism are reported to be associated with numerous chromosomal anomalies, cases with AD must undergo cytogenetic evaluation. According to Jacquemont (2006), higher rate of deletions, duplications or translocations are reported in AD cases and they are presented with the condition of mental retardation, anomalous EEG prototypes along with seizures, muscular hypotonia, gross motor and gait tribulations or dysmorphic characteristics. Individuals not displaying dysmorphic traits also show chromosomal abnormalities. Submicroscopic copy number variations With the advent of new genetic tools it is now feasible to assess minor genetic anomaly which remains undetected by karyotyping (Henrichsen, 2009). According to Sebat et al (2007), the advent of micro-array technology has made it possible to procure a comparative genomic hybridization (array- CGH). This could also be utilized for copy number variation (CNV), which could be due to any of the chromosomal anomaly explained either by deletion, insertion, duplication or it may be due to intricate multi-variant mechanism. As the genetics of inheritance states, anomaly could be inherited from the parents or it is generated due to various other factors encompassing mutation or other environmental factors which influence the genes and hence becomes responsible for the alteration in the maternal or paternal chromosomal sets. The expression of mutation is reported only in the case of active genes as due to the altered nitrogen bases the desired protein is not synthesized and thereby the abnormal protein or the incomplete protein that is formed hampers the normal physiological pathway, affecting development or the physiology of the individual. Numerous changes could be observed due to the CNVs encompassing alteration in the transcription, which affects the formation of m-RNA which in turn affects the synthesis of proteins responsible for the formation of vital enzymes or structural components of the cells. If the process involves deletion of the chromosomal segment it may result in inability to mask recessive mutation. Deletion may also result in alteration of the chromosome function which portray a serious implication on the survival and well being of the individual. Studies carried out with the AD cases highlight the fact that AD patients display some CNVs when their genome was compared with the controls (Sebat et al, 2007). According to van der Zwaag (2009), replicated CNVs are reported to be recurrent in AD cases as compared to their control counterparts. In case of AD CNVs are prevalent on various chromosomes encompassing- 1q21, 2p16.3 (NRXN1), 3p25-26 (CNTN4), 7q36.2 (DPP6), 15q11-13 (UBE3A, OR4M2, OR4N4); 16p11.2 (MAPK3, MAZ, DOC2A, SEZ6L2, HIRIP3, IL6); 22q11.2. When compared with the CNVs reported from the cases of mental retardation or schizophrenia, AD CNVs are found to be closely related when evaluated against their control counterparts. Further, ASD explicit CNVs were not entirely pragmatic in AD cases with particular dysmorphic attributes or mental retardation but they were also reported to be present in high-functioning patients of autism with only slight dysmorphology (van der Zwaag; 2009). Genetic mechanism involved in the functional pathways of AD Classical linkage studies paved the way for molecular genetics of the present epoch. Much of the studies and identification as well as description of the genetic loci related to AD were established by means of linkage studies conducted earlier. Further, with the advent of molecular tools it is now possible to establish the fact that acoustic disorders are heterogeneous and are amalgamation of numerous monogenetic disorders comprising- fragile X syndrome, mutations in TSC1/TSC2, LAMB1, CNTNAP2, PTEN, DHCR7, SHANK3, NLGN3/4, or RPL10 (Freitag, 2010). Genetic alterations directly influence the phenotype of the individual. Genes are the basic units of inheritance and are responsible for the structural as well as functional aspects of the cells, together of the individual. It is imperative to understand that variation in the genomic sequence either by means of duplication which is responsible for producing extra copies of protein or deletion where the gene is not expressed hence the related protein is not being synthesized causing deficiency of the protein. This deficiency results in either altered cellular morphology or the cellular physiology eventually causing disorder in the individual. Small deletion or duplication or translocation of the chromosome alters the transcription process, resulting in the formation of defective or insufficient protein which is responsible for misrepresented physiological pathway which was dependent on that protein (Snustad, 2005). Similar mechanism is applicable in all the physiological processes, which are responsible for varied chromosomal or other physiological anomalies. In case of AD, serotonin-transporter gene SLC6A4 plays a vital role both as AD susceptible gene and also as a second-site modifier gene (Bartlett et al, 2005). According to Page et al, (2009), PTEN haploinsufficient mice were modified SLC6A4 haploinsufficiency, highlighting the role of PTEN in maintaining genomic constancy. According to Stiles (2009), PTEN haploinsufficiency may enhance the prospects of a secondary modifying incident, like a CNV in a chromosomal region pertinent to AD. According to Abrahams (2008), recent genetic pronouncements in AD, highlight that mutations or widespread variants in genes encoding for gene products and are involved in various cellular mechanisms such as cell–cell interaction and synaptic function, together with development of dendritic spines, neuronal migration and growth, or excitatory and inhibitory neurotransmission are causes of AD. Cellular interaction and synaptic function involves various pathways namely- NRXNs, NLNGs, CNTN3/4, CNTNAP2, and SHANK3. Besides, the FMR protein, absent in fragile X syndrome, amends dendritic spine development and synaptic plasticity by restraining mGluR1/5 mediated dendritic protein synthesis (Hagerman, 2009). On the other hand, neuronal migration and proliferation are subjected to gene products of LAMB1, EN2 or the MET receptor tyrosine kinase gene. The mTor/PI3-kinase (PI3K) pathway comprises PTEN, TSC1/2, along with other genes associated with CNVs in AD cases (Cusco et al, 2009). The process is known to play an imperative role in the neuronal cell growth. The products of the gene directly affect the regulation of excitatory neurotransmission as well as inhibitory neurotransmission are glutamate receptors and GABA receptors. Any imbalance in the excitatory or inhibitory mechanisms of neurotransmission results in anomaly. E.g. in fragile X syndrome, an imbalance was observed in this neurotransmission mechanisms (Freitag, 2010). According to Nishimura et al (2007), gene expression can differentiate between ASD cases caused by known genetic abrasion and recognize widespread pathways that were confirmed both in neural tissues and cases of idiopathic autism. Their findings described 68 molecules which are diversely articulated in cells from fragile X syndrome and 15q duplication cases reported for ASD as compared to their controls. Further, the study identified cytoplasmic FMR1 interacting protein 1 (CYFIP1; an interactor of fragile X protein), janus kinase and microtubule interacting protein 1 (JAKMIP1, also known as MARLIN1, which traffics gamma-aminobutyric acid receptors). Similar studies are also on the way to highlight the expression of genes in the peripheral blood to classify biomarkers or pathophysiological pathways in ASDs and associated neurodevelopmental disorders (Bittel, 2007). Genetic Counselling Genetic counselling is the most imperative aspect of acoustic disorders as appropriate guidance to the susceptible couple could save them from falling into severe complications that are projected by the autism case. Although it is highly challenging but in the present scenario where the competition is tough and survival is difficult, it must be carefully assessed in favor of the family and also for the medical condition (Freitag, 2010). The chief motive of the counselling is to provide the parents a complete information about the possible outcomes of having the ward with genetic abnormality. Genetic counselling provides an estimate of the health implications and recurrence risk of the acoustic disorder. Genetic counselling is more of the psychological intervention, an aid to adapt and adjust with the connotations of the acoustic disorders in the family (Freitag, 2010). Genetic counselling is mostly based on the results procured after the complete family study. the recurrence rate ranges from 2 -8%. As no particular cause of the condition could be established so far, based on the genetic analysis of the family, including parents and the children, it is imperative to safeguard the family from inviting troubles for self and for their other child/ children. The calculated risk must be explained to the parents (Freitag, 2010). If one of the child is suffering from the autism or other associated acoustic disorder it is imperative to take utmost care of the child (Freitag, 2010). Conclusion Acoustic disorders are gaining prevalence in the present epoch, the precise reason could not be established so far but the genetic basis of the conditions could be formulated because of the various studies that are being carried out across the globe in different cultural and environmental conditions. AD are found to be of high-heritability but no accurate methodology for the diagnoses and treatment of the condition could be established and it is therefore becoming a challenging topic for the researchers, pediatricians and also for the social workers. There is currently no cure for the autism. Behavior interventions involving psychotherapies may be of some help to the acoustic cases, together with the medication. Vitamin B6 and magnesium are known to be vital components for the neurotransmitters in the brain and therefore they are recommended in case of autism. Various herbal products such as Bacopa monnieri- known to be potentially rich in antioxidants help to enhance the concentration and learning ability of the individual could provide some relief to the autism condition. Other herbal medicines like Centella asiatic, which is responsible to enhance behavior in mentally challenged individuals and is known to augment IQ of the AD cases. Glycyrrhia glabra is a well known detoxifier used in China that potentially detoxifies the body. Other herbs which are known to reduce autism encompass Withania somnifera, Nelumbo nucifera etc (Autism Causes, herbal products, Ashwagandha, Bacopa). Although these herbal medicines provide some relief in reducing the symptoms of the autism condition but yet genetic basis needs to be established. The interaction of the genes with these herbs and the possible repair mechanism that the genes undergo to bring the reduction in the symptoms of AD condition require intensive research and understanding. The cellular pathways of these herbal medicines and the exact regulation of the genomic sequences need to be deciphered. As the numerous genes influence the condition of autism, the exact mechanism these herbal medicines are implicating to induce repair of the anomaly to bring improvement in the genetic product formation is of paramount significance. It becomes more crucial especially when the condition is associated with the rare variants, CNVs. Since the sample size on herbal medication is small, it is difficult to formulate the exact mechanism but if it could be established it is going to bring a great revolution in the field of acoustic disease research, a boon to those who witness the condition and those who are associated (family members) with the victims of the genetic anomaly. Future implications of the condition seem to be promising as now micro-array system brings the complete genomic analysis in the chip and the genetic anomaly could be assessed. Moreover, the drug testing could be performed for the targeted sequences. A comparative study with other mental disturbances like schizophrenia and other psychiatric disorders, could be performed to reach to a positive conclusion by developing an integral as well as significant biological models. Literature Cited 1. Abrahams, BS., Geschwind, DH., 2008. 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