Causes of autism

Many causes of autism have been proposed, but understanding of the theory of causation of autism and the other autism spectrum disorders (ASD) is incomplete. Research indicates that genetic factors predominate. The heritability of autism, however, is complex, and it is typically unclear which genes are involved. In rare cases, autism is associated with agents that cause birth defects. Many other causes have been proposed, such as childhood immunizations, but numerous epidemiological studies have shown no scientific evidence supporting any link between vaccinations and autism. Many causes of autism have been proposed, but understanding of the theory of causation of autism and the other autism spectrum disorders (ASD) is incomplete. Research indicates that genetic factors predominate. The heritability of autism, however, is complex, and it is typically unclear which genes are involved. In rare cases, autism is associated with agents that cause birth defects. Many other causes have been proposed, such as childhood immunizations, but numerous epidemiological studies have shown no scientific evidence supporting any link between vaccinations and autism. Autism involves atypical brain development which often becomes apparent in behavior and social development before a child is three years old. It can be characterized by impairments in social interaction and communication, as well as restricted interests and stereotyped behavior, and the characterization is independent of any underlying neurological defects. Other characteristics include repetitive-like tasks seen in behavior and sensory interests. This article uses the terms autism and ASD to denote classical autism and the wider dispersion of symptoms and manifestations of autism, respectively. Autism's theory of causation is incomplete. It has long been presumed that there is a common cause at the genetic, cognitive, and neural levels for autism's characteristic triad of symptoms. However, there is increasing suspicion among researchers that autism does not have a single cause, but is instead a complex disorder with a set of core aspects that have distinct causes. Different underlying brain dysfunctions have been hypothesized to result in the common symptoms of autism, just as completely different brain problems result in intellectual disability. The terms autism or ASDs capture the wide range of disease processes at work. Although these distinct causes have been hypothesized to often co-occur, it has also been suggested that the correlation between the causes has been exaggerated. The number of people known to have autism has increased dramatically since the 1980s, at least partly due to changes in diagnostic practice. It is unknown whether prevalence has increased as well. The consensus among mainstream autism researchers is that genetic factors predominate. Environmental factors that have been claimed to contribute to autism or exacerbate its symptoms, or that may be important to consider in future research, include certain foods, infectious disease, heavy metals, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, and illicit drugs. Among these factors, vaccines have attracted much attention, as parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks. However, there is overwhelming scientific evidence showing no causal association between the measles-mumps-rubella (MMR) vaccine and autism, and there is no scientific evidence that the vaccine preservative thiomersal causes autism. Genetic factors may be the most significant cause for autism spectrum disorders. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. However, this may be an overestimation, as new twin studies estimate the heritability at between 60–90%. Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%. However, in spite of the strong heritability, most cases of ASD occur sporadically with no recent evidence of family history. It has been hypothesized that spontaneous de novo mutations in the father's sperm or mother's egg contribute to the likelihood of developing autism. There are two lines of evidence that support this hypothesis. First, individuals with autism have significantly reduced fecundity, they are 20 times less likely to have children than average, thus curtailing the persistence of mutations in ASD genes over multiple generations in a family. Second, the likelihood of having a child develop autism increases with advancing paternal age, and mutations in sperm gradually accumulate throughout a man's life. The first genes to be definitively shown to contribute to risk for autism were found in the early 1990s by researchers looking at gender-specific forms of autism caused by mutations on the X chromosome.An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder. Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal. Besides these early examples, the role of de novo mutations in ASD first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome. CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo CNVs occur at a significantly higher rate in sporadic cases of autism as compared to the rate in their typically developing siblings and unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in ASD than in controls and contribute to approximately 5–10% of cases. Based on these studies, there are predicted to be 130–234 ASD-related CNV loci. The first whole genome sequencing study to comprehensively catalog de novo structural variation at a much higher resolution than DNA microarray studies has shown that the mutation rate is approximately 20% and not elevated in autism compared to sibling controls. However, structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies. CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the 'exome'). These studies found that de novo gene inactivating mutations were observed in approximately 20% of individuals with autism, compared to 10% of unaffected siblings, suggesting the etiology of ASD is driven by these mutations in around 10% of cases. There are predicted to be 350-450 genes that significantly increase susceptibility to ASDs when impacted by inactivating de novo mutations. A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene. Therefore approximately 30% of individuals with autism have a spontaneous de novo large CNV that deletes or duplicates genes, or mutation that changes the amino acid code of an individual gene. A further 5–10% of cases have inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.