Heritability of autism

Short description: none

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.[1][2]

Studies of twins from 1977 to 1995 estimated the heritability of autism to be more than 90%; in other words, that 90% of the differences between autistic and non-autistic individuals are due to genetic effects.[3] When only one identical twin is autistic, the other often has learning or social disabilities.[4] For adult siblings, the likelihood of having one or more features of the broader autism phenotype might be as high as 30%,[5] much higher than the likelihood in controls.[6]

A variety of genetic associations with autism spectrum disorder have been reported. These associations are much more common than rare mutations, and each individual variant has a relatively small effect.

Though genetic linkage analysis have been inconclusive,[7] many association analyses have discovered genetic variants associated with autism.[8] For each autistic individual, mutations in many genes are typically implicated. Mutations in different sets of genes may be involved in different autistic individuals. There may be significant interactions among mutations in several genes, or between the environment and mutated genes. By identifying genetic markers inherited with autism in family studies, numerous candidate genes have been located, most of which encode proteins involved in neural development and function.[9][10] However, for most of the candidate genes, the actual mutations that increase the likelihood for autism have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to single chromosome abnormalities such as fragile X syndrome or 22q13 deletion syndrome.[11][12]

10-15% of autism cases may result from single gene disorders or copy number variations (CNVs)—spontaneous alterations in the genetic material during meiosis that delete or duplicate genetic material.[13][14][15] These sometimes result in syndromic autism, as opposed to the more common idiopathic autism.[16][17] Sporadic (non-inherited) cases have been examined to identify candidate genetic loci involved in autism. A substantial fraction of autism may be highly heritable but not inherited: that is, the mutation that causes the autism is not present in the parental genome.[18]

Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array CGH improves,[18] several results in this area have been described incautiously, possibly misleading the public into thinking that a large proportion of autism is caused by CNVs and is detectable via array CGH, or that detecting CNVs is tantamount to a genetic diagnosis.[19] The Autism Genome Project database contains genetic linkage and CNV data that connect autism to genetic loci and suggest that every human chromosome may be involved.[20] It may be that using autism-related sub-phenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci.[21]

## Contents

* 1 Twin studies
* 2 Sibling studies
* 3 Other family studies
* 4 Twinning risk
* 5 Proposed models
* 5.1 Single genes
* 5.2 Multigene interactions
* 5.3 Two family types
* 5.4 Epigenetic
* 5.5 Genomic imprinting
* 5.6 Environmental interactions
* 5.7 Sex bias
* 6 Candidate gene loci
* 6.1 Primary
* 6.2 Others
* 7 References
* 8 Further reading
* 9 External links

## Twin studies

Twin studies are a helpful tool in determining the heritability of disorders and human traits in general. They involve determining concordance of characteristics between identical (monozygotic or MZ) twins and between fraternal (dizygotic or DZ) twins. Possible problems of twin studies are: (1) errors in diagnosis of monozygocity, and (2) the assumption that social environment sharing by DZ twins is equivalent to that of MZ twins.

A condition that is environmentally caused without genetic involvement would yield a concordance for MZ twins equal to the concordance found for DZ twins. In contrast, a condition that is completely genetic in origin would theoretically yield a concordance of 100% for MZ pairs and usually much less for DZ pairs depending on factors such as the number of genes involved and assortative mating.

An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome (IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively.[22] An example of a human characteristics that is extremely heritable is eye color, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.[23]

Identical twin studies put autism's heritability in a range between 36% and 95.7%, with concordance for a broader phenotype usually found at the higher end of the range.[24] Autism concordance in siblings and fraternal twins is anywhere between 0 and 23.5%. This is more likely 2–4% for classic autism and 10–20% for a broader spectrum. Assuming a general-population prevalence of 0.1%, the risk of classic autism in siblings is 20- to 40-fold that of the general population.

Notable twin studies have attempted to shed light on the heritability of autism.

A small scale study in 1977 was the first of its kind to look into the heritability of autism. It involved 10 DZ twins and 11 MZ twins in which at least one twin in each pair showed infantile autism. It found a concordance of 36% in MZ twins compared to 0% for DZ twins. Concordance of "cognitive abnormalities" was 82% in MZ pairs and 10% for DZ pairs. In 12 of the 17 pairs discordant for autism, a biological hazard was believed to be associated with the condition.[25]

A 1979 case report discussed a pair of identical twins concordant for autism. The twins developed similarly until the age of 4, when one of them spontaneously improved. The other twin, who had had infrequent seizures, remained autistic. The report noted that genetic factors were not "all important" in the development of twins.[26]

In 1985, a study of twins enrolled with the UCLA Registry for Genetic Studies found a concordance of 95.7% for autism in 23 pairs of MZ twins, and 23.5% for 17 DZ twins.[27]

In a 1989 study, Nordic countries were screened for cases of autism. Eleven pairs of MZ twins and 10 of DZ twins were examined. Concordance of autism was found to be 91% in MZ and 0% in DZ pairs. The concordances for "cognitive disorder" were 91% and 30% respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress.[28]

A British twin sample was reexamined in 1995 and a 60% concordance was found for autism in MZ twins vs. 0% concordance for DZ. It also found 92% concordance for a broader spectrum in MZ vs. 10% for DZ. The study concluded that "obstetric hazards usually appear to be consequences of genetically influenced abnormal development, rather than independent aetiological factors."[29]

A 1999 study looked at social cognitive skills in the general-population of children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.[30]

In 2000, a study looked at reciprocal social behavior in general-population identical twins. It found a concordance of 73% for MZ, i.e. "highly heritable", and 37% for DZ pairs.[31]

A 2004 study looked at 16 MZ twins and found a concordance of 43.75% for "strictly defined autism". Neuroanatomical differences (discordant cerebellar white and grey matter volumes) between discordant twins were found. The abstract notes that in previous studies 75% of the non-autistic twins displayed the broader phenotype.[32]

Another 2004 study examined whether the characteristic symptoms of autism (impaired social interaction, communication deficits, and repetitive behaviors) show decreased variance of symptoms among monozygotic twins compared to siblings in a sample of 16 families. The study demonstrated significant aggregation of symptoms in twins. It also concluded that "the levels of clinical features seen in autism may be a result of mainly independent genetic traits."[33]

An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.[34]

One critic of the pre-2006 twin studies said that they were too small and their results can be plausibly explained on non-genetic grounds.[35]

## Sibling studies

A study of 99 autistic probands which found a 2.9% concordance for autism in siblings, and between 12.4% and 20.4% concordance for a "lesser variant" of autism.[6]

A study of 31 siblings of autistic children, 32 siblings of children with developmental delay, and 32 controls. It found that the siblings of autistic children, as a group, "showed superior spatial and verbal span, but a greater than expected number performed poorly on the set-shifting, planning, and verbal fluency tasks."[36]

A 2005 Danish study looked at "data from the Danish Psychiatric Central Register and the Danish Civil Registration System to study some risk factors of autism, including place of birth, parental place of birth, parental age, family history of psychiatric disorders, and paternal identity." It found an overall prevalence rate of roughly 0.08%. Prevalence of autism in siblings of autistic children was found to be 1.76%. Prevalence of autism among siblings of children with Asperger syndrome or PDD was found to be 1.04%. The risk was twice as high if the mother had been diagnosed with a psychiatric disorder. The study also found that "the risk of autism was associated with increasing degree of urbanisation of the child's place of birth and with increasing paternal, but not maternal, age."[37]

A study in 2007 looked at a database containing pedigrees of 86 families with two or more autistic children and found that 42 of the third-born male children showed autistic symptoms, suggesting that parents had a 50% chance of passing on a mutation to their offspring. The mathematical models suggest that about 50% of autistic cases are caused by spontaneous mutations. The simplest model was to divide parents into two risk classes depending on whether the parent carries a pre-existing mutation that causes autism; it suggested that about a quarter of autistic children have inherited a copy number variation from their parents.[38]

## Other family studies

A 1994 study looked at the personalities of parents of autistic children, using parents of children with Down syndrome as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive" compared to parents whose children did not have autism.[39]

A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.[40]

Autism was found to occur more often in families of physicists, engineers and scientists. 12.5% of the fathers and 21.2% of the grandfathers (both paternal and maternal) of children with autism were engineers, compared to 5% of the fathers and 2.5% of the grandfathers of children with other syndromes.[41] Other studies have yielded similar results.[42][43] Findings of this nature have led to the coinage of the term "geek syndrome".[44]

A 2001 study of brothers and parents of autistic boys looked into the phenotype in terms of one current cognitive theory of autism. The study raised the possibility that the broader autism phenotype may include a "cognitive style" (weak central coherence) that can confer information-processing advantages.[45]

A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents.[46] Another 2005 study focused on sub-threshold autistic traits in the general population. It found that correlation for social impairment or competence between parents and their children and between spouses is about 0.4.[47]

A 2005 report examined the family psychiatric history of 58 subjects with Asperger syndrome (AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia. Thirty five (60%) had a family history of depression. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.[48] According to a 2022 study held on 86 mother-child dyads across 18 months, "prior maternal depression didn’t predict child behavior problems later."[49]

## Twinning risk

It has been suggested that the twinning process itself is a risk factor in the development of autism, presumably due to perinatal factors.[50] However, three large-scale epidemiological studies have refuted this idea.[3][51] These studies took place in California, Sweden, and Australia.[51] One study done in Western Australia, utilized the Maternal and Child Health Research Database that houses birth records for all infants born, including infants and later children diagnosed with autism spectrum disorder. During this study, the population analyzed for the incidence of Autism Spectrum Disorder was restricted to those children with birth years between 1980 and 1995. The focus was on the incidence of autism spectrum disorder in the twin population in comparison to the non twin population. The following two studies,[29][51] explored the risk of Autism spectrum disorder in the twin population. The conclusion that the twinning process alone is not a risk factor was drawn.[51] In these studies the data exemplified that both MZ twins will have autism spectrum disorder, but only one of the DZ twins will have autism spectrum disorder with an incidence rate of 90% in MZ twins compared to 0% in DZ twins.[29] The high symmetry in MZ twins can explain the high symmetry of autism spectrum disorder in MZ twins outcome compared to DZ twins and non twin siblings.[51]

## Proposed models

Twin and family studies show that autism is a highly heritable condition, but they have left many questions for researchers, most notably

* Why is fraternal twin concordance so low considering that identical twin concordance is high?
* Why are parents of autistic children typically non-autistic?
* Which factors could be involved in the failure to find a 100% concordance in identical twins?
* Is profound intellectual disability a characteristic of the genotype or something totally independent?

Clues to the first two questions come from studies that have shown that at least 30% of individuals with autism have spontaneous de novo mutations that occurred in the father's sperm or mother's egg that disrupt important genes for brain development. These spontaneous mutations are likely to cause autism in families where there is no family history of the disorder.[52] The concordance between identical twins isn't quite 100% for two reasons, because these mutations have variable 'expressivity' and their effects manifest differently due to chance effects, epigenetic, and environmental factors. Also spontaneous mutations can potentially occur specifically in one embryo and not the other after conception.[53] The likelihood of developing intellectual disability is dependent on the importance of the gene to brain development and how the mutation changes this function, also playing a role is the genetic and environmental background upon which a mutation occurs.[54] The recurrence of the same mutations in multiple individuals affected by autism has led Brandler and Sebat to suggest that the spectrum of autism is breaking up into quanta of many different genetic disorders.[54]

### Single genes

The most parsimonious explanation for cases of autism where a single child is affected and there is no family history or affected siblings is that a single spontaneous mutation that impacts one or multiple genes is a significant contributing factor.[54][55] Tens of individual genes or mutations have been definitively identified and are cataloged by the Simons Foundation Autism Research Initiative.[56][57]

Examples of autism that has arisen from a rare or de novo mutation in a single-gene or locus include the neurodevelopmental disorders fragile X syndrome, 22q13 deletion syndrome, and 16p11.2 deletion syndrome.[58]

Deletion (1), duplication (2) and inversion (3) are all chromosome abnormalities that have been implicated in autism.[18]

These mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. For example, carriers of the 16p11.2 deletion have a mean IQ 32 points lower than their first-degree relatives that do not carry the deletion, however only 20% are below the threshold IQ of 70 for intellectual disability, and only 20% have autism.[59][60] Around 85% have a neurobehavioral diagnosis, including autism, ADHD, anxiety disorders, mood disorders, gross motor delay, and epilepsy, while 15% have no diagnosis.[60] Alongside these neurobehavioral phenotypes, the 16p11.2 deletions / duplications have been associated with macrocephaly / microcephaly, body weight regulation, and the duplication in particular is associated with schizophrenia.[59][61][62] Controls that carry mutations associated with autism or schizophrenia typically present with intermediate cognitive phenotypes or fecundity compared to neurodevelopmental cases and population controls.[63] Therefore, a single mutation can have multiple different effects depending on other genetic and environmental factors.

### Multigene interactions

In this model, autism often arises from a combination of common, functional variants of genes. Each gene contributes a relatively small effect in increasing the risk of autism. In this model, no single gene directly regulates any core symptom of autism such as social behavior. Instead, each gene encodes a protein that disrupts a cellular process, and the combination of these disruptions, possibly together with environmental influences,[64] affect key developmental processes such as synapse formation. For example, one model is that many mutations affect MET and other receptor tyrosine kinases, which in turn converge on disruption of ERK and PI3K signaling.[58]

### Two family types

In this model most families fall into two types: in the majority, sons have a low risk of autism, but in a small minority their risk is near 50%. In the low-risk families, sporadic autism is mainly caused by spontaneous mutation with poor penetrance in daughters and high penetrance in sons. The high-risk families come from (mostly female) children who carry a new causative mutation but are unaffected and transmit the dominant mutation to grandchildren.[38]

### Epigenetic

Main page: Biology:Epigenetics of autism

Several epigenetic models of autism have been proposed.[65] These are suggested by the occurrence of autism in individuals with fragile X syndrome, which arises from epigenetic mutations, and with Rett syndrome, which involves epigenetic regulation factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.[66]

### Genomic imprinting

Genomic imprinting models have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD.[67] One hypothesis is that autism is in some sense diametrically opposite to schizophrenia and other psychotic-spectrum conditions, that alterations of genomic imprinting help to mediate the development of these two sets of conditions, and that ASD involves increased effects of paternally expressed genes, which regulate overgrowth in the brain, whereas schizophrenia involves maternally expressed genes and undergrowth.[68]

### Environmental interactions

Though autism's genetic factors explain most of autism risk, they do not explain all of it. A common hypothesis is that autism is caused by the interaction of a genetic predisposition and an early environmental insult.[69] Several theories based on environmental factors have been proposed to address the remaining risk. Some of these theories focus on prenatal environmental factors, such as agents that cause birth defects; others focus on the environment after birth, such as children's diets. All known teratogens (agents that cause birth defects) related to the risk of autism appear to act during the first eight weeks from conception, strong evidence that autism arises very early in development.[70] Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies,[71] extensive searches are underway.[72]

### Sex bias

Autism spectrum disorder affects all races, ethnicities, and socioeconomic groups. Still, more males than females are affected across all cultures,[73] the ratios of males-to-females is appropriately 3 to 1.[74] A study analyzed the Autism Genetics Resource Exchange (AGRE database), which holds resources, research, and records of autism spectrum disorder diagnosis. In this study, it was concluded that when a spontaneous mutation causes autism spectrum disorder (ASD), there is high penetrance in males and low penetrance in females.[74][75] A study published in 2020 explored the reason behind this idea further.[76] It is commonly known that the main difference between males and females is the fact that males have one X and one Y sex chromosome whereas female have two X chromosomes. This leads to the idea that there is a gene on the X chromosome that is not on the Y that is involved with the sex bias of ASD.[76][73]

In another study, it has been found that the gene called NLGN4, when mutated, can cause ASD.[77] This gene and other NLGN genes are important for neuron communications.[73] This NLGN4 gene is found on both the X (NLGN4X) and the Y (NLGN4Y) chromosome. The sex chromosomes are 97% identical.[73][76] It has been determined that most of the mutations that occur are located on the NLGN4X gene.[73][77] Research into the differences between NLGN4X and NLGN4Y found that the NLGN4Y protein has poor surface expectations and poor synapses regulations, leading to poor neuron communication.[73][76] Researchers concluded that males have a higher incidence of autism when the mechanism is NLGN4X-associated.[73] This association was concluded since females have two X chromosomes; if there is a mutation in a gene on an X chromosome, the other X chromosome can be used to compensate for the mutation. Whereas males have only one X chromosome, meaning that if there is a mutation in a gene on an X chromosome, then that is the only copy of the gene and it will be used. The genomic difference between males and females is one mechanism that leads to the higher incidence of ASD in males.[73][76][77]

## Candidate gene loci

Known genetic syndromes, mutations, and metabolic diseases account for up to 20% of autism cases.[78] A number of alleles have been shown to have strong linkage to the autism phenotype. In many cases the findings are inconclusive, with some studies showing no linkage. Alleles linked so far strongly support the assertion that there is a large number of genotypes that are manifested as the autism phenotype. At least some of the alleles associated with autism are fairly prevalent in the general population, which indicates they are not rare pathogenic mutations. This also presents some challenges in identifying all the rare allele combinations involved in the etiology of autism.

A 2008 study compared genes linked with autism to those of other neurological diseases, and found that more than half of known autism genes are implicated in other disorders, suggesting that the other disorders may share molecular mechanisms with autism.[79]

### Primary

Conciatori et al.. (2004) found an association of HOXA1 with increased head circumference.[86] A number of studies have found no association with autism.[87][88][89] The possibility remains that single allelic variants of the HOXA1 gene are insufficient alone to trigger the developmental events in the embryo now associated with autistic spectrum conditions. Tischfield et al.. published a paper which suggests that because HOXA1 is implicated in a wide range of developmental mechanisms, a model involving multiple allelic variants of HOXA1 in particular may provide useful insights into the heritability mechanisms involved.[90] Additionally, Ingram et al.. alighted upon additional possibilities in this arena.[91] Transgenic mouse studies indicate that there is redundancy spread across HOX genes that complicate the issue, and that complex interactions between these genes could play a role in determining whether or not a person inheriting the requisite combinations manifests an autistic spectrum condition[92]—transgenic mice with mutations in both HOXA1 and HOXB1 exhibit far more profound developmental anomalies than those in which only one of the genes differs from the conserved 'norm'. In Rodier's original work, teratogens are considered to play a part in addition, and that the possibility remains open for a range of teratogens to interact with the mechanisms controlled by these genes unfavourably (this has already been demonstrated using valproic acid, a known teratogen, in the mouse model).[93] The objective of the study was to locate specific brain cells involved in autism to find regions in the genome linked to autism susceptibility genes. The focus of the research was copy number variations (CNVs), extra or missing parts of genes. Each person does not actually have just an exact copy of genes from each parent. Each person also has occasional multiple copies of one or more genes or some genes are missing altogether. The research team attempted to locate CNVs when they scanned the DNA. Neurexin 1 is one of the genes that may be involved in communication between nerve cells (neurons). Neurexin 1 and other genes like it are very important in determining how the brain is connected from cell to cell, and in the chemical transmission of information between nerve cells. These genes are particularly active very early in brain development, either in utero or in the first months or couple of years of life. In some families their autistic child had only one copy of the neurexin 1 gene. Besides locating another possible genetic influence (the findings were statistically insignificant), the research also reinforced the theory that autism involves many forms of genetic variations. A 2008 study implicated the neurexin 1 gene in two independent subjects with ASD, and suggested that subtle changes to the gene might contribute to susceptibility to ASD.[106] A Neurexin 1 deletion has been observed occurring spontaneously in an unaffected mother and was passed on to an affected child, suggesting that the mutation has incomplete penetrance.[107] Gene | OMIM/# | Locus | Description

|
|
|

CDH9, CDH10 |  | 5p14.1 | A 2009 pair of genome-wide association studies found an association between autism and six single-nucleotide polymorphisms in an intergenic region between CDH10 (cadherin 10) and CDH9 (cadherin 9). These genes encode neuronal cell-adhesion molecules, implicating these molecules in the mechanism of autism.[80]
MAPK3 |  | 16p11.2 | A 2008 study observed a de novo deletion of 593 kb on this chromosome in about 1% of persons with autism, and similarly for the reciprocal duplication of the region.[81] Another 2008 study also found duplications and deletions associated with ASD at this locus.[82] This gene encodes ERK1, one of the extracellular signal regulated kinase subfamily of mitogen-activated protein kinases which are central elements of an intracellular signaling pathways that transmits signals from cell surfaces to interiors. 1% of autistic children have been found to have either a loss or duplication in a region of chromosome 16 that encompasses the gene for ERK1. A similar disturbance in this pathway is also found in neuro-cardio-facial-cutaneous syndromes (NCFC), which are characterized by cranio-facial development disturbances that also can be found in some cases of autism.[83]
EN2 |  | 7q36.2 | Engrailed 2 is believed to be associated with cerebellar development. Benayed et al.. (2005) estimate that this gene contributes to as many as 40% of ASD cases, about twice the prevalence of the general population.[84] But at least one study has found no association.[85]
PRKCB1 |  | 16p11.2 | Philippi et al. (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated.[94]
TAOK2 |  | 16p11.2 | Richter et al. (2018) found a strong association between this gene and autism.[95]
UBE3A |  | 15q11.2–q13 | The maternally expressed imprinted gene UBE3A has been associated with Angelman syndrome. MeCP2 deficiency results in reduced expression of UBE3A in some studies.[96]
SHANK3 (ProSAP2) |  | 22q13 | The gene called SHANK3 (also designated ProSAP2) regulates the structural organization of neurotransmitter receptors in post-synaptic dendritic spines making it a key element in chemical binding crucial to nerve cell communication.[97] SHANK3 is also a binding partner of chromosome 22q13 (i.e. a specific section of Chromosome 22) and neuroligin proteins; deletions and mutations of SHANK3, 22q13 (i.e. a specific section of Chromosome 22) and genes encoding neuroligins have been found in some people with autism spectrum disorders.[98]

Mutations in the SHANK3 gene have been strongly associated with the autism spectrum disorders. If the SHANK3 gene is not adequately passed to a child from the parent (haploinsufficiency) there will possibly be significant neurological changes that are associated with yet another gene, 22q13, which interacts with SHANK3. Alteration or deletion of either will effect changes in the other.[98]

A deletion of a single copy of a gene on chromosome 22q13 has been correlated with global developmental delay, severely delayed speech or social communication disorders and moderate to profound delay of cognitive abilities. Behavior is described as "autistic-like" and includes high tolerance to pain and habitual chewing or mouthing[98] (see also 22q13 deletion syndrome). This appears to be connected to the fact that signal transmission between nerve cells is altered with the absence of 22q13.

SHANK3 proteins also interact with neuroligins at the synapses of the brain further complicating the widespread effects of changes at the genetic level and beyond.[99]

NLGN3 | Online Mendelian Inheritance in Man (OMIM) 300425, AUTSX1 | Xq13 | Neuroligin is a cell surface protein (homologous to acetylcholinesterase and other esterases) that binds to synaptic membranes.[100] Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory);[101] In this way, neuroligins help to ensure signal transitions between nerve cells. Neuroligins also regulate the maturation of synapses and ensure there are sufficient receptor proteins on the synaptic membrane.

Mice with a neuroligin-3 mutation exhibit poor social skills but increased intelligence.[102] Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders.[99] However, a 2008 study found no evidence for involvement of neuroligin-3 and neuroligin-4x with high-functioning ASD.[103]

MET |  | 7q31 | The MET gene (MET receptor tyrosine kinase gene) linked to brain development, regulation of the immune system, and repair of the gastrointestinal system, has been linked to autism. This MET gene codes for a protein that relays signals that turn on a cell's internal machinery. Impairing the receptor's signaling interferes with neuron migration and disrupts neuronal growth in the cerebral cortex and similarly shrinks the cerebellum—abnormalities also seen in autism.[104]

It is also known to play a key role in both normal and abnormal development, such as cancer metastases. A mutation of the gene, rendering it less active, has been found to be common amongst children with autism.[104] Mutation in the MET gene demonstrably raises risk of autism by 2.27 times.[105]

CNTNAP2 |  | 7q35-q36 | Multiple 2008 studies have identified a series of functional variants in the CNTNAP2 gene, a member of the neurexin superfamily, that implicate it as contributing to autism.[64][108][109][110]
GSTP1 |  | 11q13 | A 2007 study suggested that the GSTP1*A haplotype of the glutathione S-transferase P1 gene (GSTP1) acts in the mother during pregnancy and increases the likelihood of autism in the child.[111]
PRL, PRLR, OXTR |  | multiple | A 2014 meta-analysis found significant associations between autism and several single-nucleotide polymorphisms in the OXTR gene.[112]

### Others

There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genome-wide scans have been performed identifying markers across many chromosomes.[113][114][115]

A few examples of loci that have been studied are the 17q21 region,[116][117] the 3p24-26 locus,[113] PTEN,[118] 15q11.2–q13[96] and deletion in the 22q11.2 area.[119]

Homozygosity mapping in pedigrees with shared ancestry and autism incidence has recently implicated the following candidate genes: PCDH10, DIA1 (formerly known as C3ORF58), NHE9, CNTN3, SCN7A, and RNF8. Several of these genes appeared to be targets of MEF2,[120][121] one of the transcription factors known to be regulated by neuronal activity[122] and that itself has also recently been implicated as an autism-related disorder candidate gene.[123]

## References

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2. ↑ Weiner, Daniel J.; Wigdor, Emilie M.; Ripke, Stephan; Walters, Raymond K.; Kosmicki, Jack A.; Grove, Jakob; Samocha, Kaitlin E.; Goldstein, Jacqueline I. et al. (2017-05-15). "Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders" (in en). Nature Genetics 49 (7): 978–985. doi:10.1038/ng.3863. ISSN 1546-1718. PMID 28504703. ""Common polygenic variation, distributed across the genome, accounts for at least 20% of ASD liability. De novo single-nucleotide and copy number variants can have a strong effect on the individuals who carry them but account for less liability at a population level (<10%)."".
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11. ↑ "Specific genetic disorders and autism: clinical contribution towards their identification". Journal of Autism and Developmental Disorders 35 (1): 103–16. February 2005. doi:10.1007/s10803-004-1038-2. PMID 15796126.
12. ↑ "The study of autism as a distributed disorder". Mental Retardation and Developmental Disabilities Research Reviews 13 (1): 85–95. 2007. doi:10.1002/mrdd.20141. PMID 17326118.
13. ↑ "Copy-number variations associated with neuropsychiatric conditions". Nature 455 (7215): 919–23. October 2008. doi:10.1038/nature07458. PMID 18923514. Bibcode: 2008Natur.455..919C.
14. ↑ "Rare structural variation of synapse and neurotransmission genes in autism". Molecular Psychiatry 17 (4): 402–11. April 2012. doi:10.1038/mp.2011.10. PMID 21358714.
15. ↑ Devlin, Bernie; Scherer, Stephen W (2012-06-01). "Genetic architecture in autism spectrum disorder" (in en). Current Opinion in Genetics & Development. Molecular and genetic bases of disease 22 (3): 229–237. doi:10.1016/j.gde.2012.03.002. ISSN 0959-437X. PMID 22463983. https://www.sciencedirect.com/science/article/pii/S0959437X12000366.
16. ↑ Sztainberg, Yehezkel; Zoghbi, Huda Y. (2016-10-26). "Lessons learned from studying syndromic autism spectrum disorders" (in en). Nature Neuroscience 19 (11): 1408–1417. doi:10.1038/nn.4420. ISSN 1546-1726. PMID 27786181. https://www.nature.com/articles/nn.4420.
17. ↑ Benvenuto, Arianna; Moavero, Romina; Alessandrelli, Riccardo; Manzi, Barbara; Curatolo, Paolo (2009-08-01). "Syndromic autism: causes and pathogenetic pathways" (in en). World Journal of Pediatrics 5 (3): 169–176. doi:10.1007/s12519-009-0033-2. ISSN 1867-0687. PMID 19693459. https://doi.org/10.1007/s12519-009-0033-2.
18. ↑ 18.0 18.1 18.2 "Autism: highly heritable but not inherited". Nature Medicine 13 (5): 534–6. May 2007. doi:10.1038/nm0507-534. PMID 17479094.
19. ↑ "Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research". Genetics in Medicine 9 (9): 626–31. September 2007. doi:10.1097/GIM.0b013e3181485688. PMID 17873651.
20. ↑ Cite error: Invalid `<ref>` tag; no text was provided for refs named `AGPC2007`
21. ↑ "Genome-wide linkage analyses of quantitative and categorical autism subphenotypes". Biological Psychiatry 64 (7): 561–70. October 2008. doi:10.1016/j.biopsych.2008.05.023. PMID 18632090.
22. ↑ "Genetic influences in irritable bowel syndrome: a twin study". The American Journal of Gastroenterology 100 (6): 1340–4. June 2005. doi:10.1111/j.1572-0241.2005.41700.x. PMID 15929767.
23. ↑ "Eye color changes past early childhood. The Louisville Twin Study". Archives of Ophthalmology 115 (5): 659–63. May 1997. doi:10.1001/archopht.1997.01100150661017. PMID 9152135.
24. ↑ Twin studies (concordance in brackets):
* (0.8–1) "The Neurobiology of Infantile Autism". NARSAD News Letter. National Alliance for Research on Schizophrenia and Depression. http://www.narsad.org/news/newsletter/specialreports/archautism.html.
* (0.8) "CDC Reports a higher than expected prevalence of autism in Brick Township". Autism Biomedical Information Network. 3 May 2000. http://www.autism-biomed.org/bricktwn.htm.
* (0.91–0.93) "Written testimony Public Health Subcommittee, United States Senate". 16 September 1999. http://faculty.washington.edu/dawson/Advocacy/Congress.html.
* (0.9) "Study points to chromosome site of autism gene". UNC-CH School of Medicine. http://www.parentsofallergicchildren.org/autism2.htm.
* (0.6–0.92) "The genetics of autism". Pediatrics 113 (5): e472-86. May 2004. doi:10.1542/peds.113.5.e472. PMID 15121991.
* (0.6–0.8) "[Current status of autism studies]" (in Japanese). Seishin Shinkeigaku Zasshi = Psychiatria et Neurologia Japonica 103 (1): 64–75. 2001. PMID 11383012.
25. ↑ "Infantile autism: a genetic study of 21 twin pairs". Journal of Child Psychology and Psychiatry, and Allied Disciplines 18 (4): 297–321. September 1977. doi:10.1111/j.1469-7610.1977.tb00443.x. ISSN 0021-9630. OCLC 01307942. PMID 562353.
26. ↑ "Monozygotic twins with early infantile autism. A case report". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde 55 (23): 955–7. June 1979. PMID 572995.
27. ↑ "Concordance for the syndrome of autism in 40 pairs of afflicted twins". The American Journal of Psychiatry 142 (1): 74–7. January 1985. doi:10.1176/ajp.142.1.74. PMID 4038442.
28. ↑ "A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden". Journal of Child Psychology and Psychiatry, and Allied Disciplines 30 (3): 405–16. May 1989. doi:10.1111/j.1469-7610.1989.tb00254.x. ISSN 0021-9630. OCLC 01307942. PMID 2745591.
29. ↑ 29.0 29.1 29.2 "Autism as a strongly genetic disorder: evidence from a British twin study". Psychological Medicine 25 (1): 63–77. January 1995. doi:10.1017/S0033291700028099. PMID 7792363.
30. ↑ "Heritability of social cognitive skills in children and adolescents". The British Journal of Psychiatry 175 (6): 559–64. December 1999. doi:10.1192/bjp.175.6.559. PMID 10789354. http://jnnp.bmj.com/content/67/6/833.4.long.
31. ↑ "Genetic structure of reciprocal social behavior". The American Journal of Psychiatry 157 (12): 2043–5. December 2000. doi:10.1176/appi.ajp.157.12.2043. PMID 11097975.
32. ↑ "Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism". The American Journal of Psychiatry 161 (3): 539–46. March 2004. doi:10.1176/appi.ajp.161.3.539. PMID 14992981.
33. ↑ "Familial symptom domains in monozygotic siblings with autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 129B (1): 76–81. August 2004. doi:10.1002/ajmg.b.30011. PMID 15274045.
34. ↑ "Genetic heterogeneity between the three components of the autism spectrum: a twin study". Journal of the American Academy of Child and Adolescent Psychiatry 45 (6): 691–699. June 2006. doi:10.1097/01.chi.0000215325.13058.9d. PMID 16721319.
35. ↑ "Autism and genetics: much ado about very little". The Missing Gene: Psychiatry, Heredity, and the Fruitless Search for Genes. Algora. 2006. ISBN 0-87586-410-4. http://www.jayjoseph.net/MissingGeneChapters.html. Retrieved 2007-07-25.
36. ↑ "Towards a cognitive phenotype for autism: increased prevalence of executive dysfunction and superior spatial span amongst siblings of children with autism". Journal of Child Psychology and Psychiatry, and Allied Disciplines 40 (5): 705–18. July 1999. doi:10.1111/1469-7610.00487. ISSN 0021-9630. OCLC 01307942. PMID 10433405.
37. ↑ "Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study". Journal of Child Psychology and Psychiatry, and Allied Disciplines 46 (9): 963–71. September 2005. doi:10.1111/j.1469-7610.2004.00391.x. ISSN 0021-9630. OCLC 01307942. PMID 16108999.
38. ↑ 38.0 38.1 "A unified genetic theory for sporadic and inherited autism". Proceedings of the National Academy of Sciences of the United States of America 104 (31): 12831–6. July 2007. doi:10.1073/pnas.0705803104. PMID 17652511. Bibcode: 2007PNAS..10412831Z.
39. ↑ "Personality characteristics of the parents of autistic individuals". Psychological Medicine 24 (3): 783–95. August 1994. doi:10.1017/S0033291700027938. PMID 7991760.
40. ↑ "Broader autism phenotype: evidence from a family history study of multiple-incidence autism families". The American Journal of Psychiatry 154 (2): 185–90. February 1997. doi:10.1176/ajp.154.2.185. PMID 9016266.
41. ↑ "Autism occurs more often in families of physicists, engineers, and mathematicians". Autism 2 (3): 296–301. 1998. doi:10.1177/1362361398023008. http://www.autismresearchcentre.com/docs/papers/1998_BCetal_Maths.pdf.
42. ↑ "Is there a link between engineering and autism?". Autism 1 (1): 153–163. 1997. doi:10.1177/1362361397011010. http://www.autismresearchcentre.com/docs/papers/1997_BCetal_Engineer.pdf.
43. ↑ "The link between autism and skills such as engineering, maths, physics and computing: a reply to Jarrold and Routh". Autism 5 (2): 223–7. June 2001. doi:10.1177/1362361301005002010. PMID 11706868. https://doi.org/10.1177/1362361301005002010. Retrieved October 5, 2020.
44. ↑ "The Geek Syndrome.". Wired Magazine. December 2001. https://www.wired.com/wired/archive/9.12/aspergers_pr.html. Retrieved December 10, 2006.
45. ↑ "Exploring the cognitive phenotype of autism: weak "central coherence" in parents and siblings of children with autism: I. Experimental tests". Journal of Child Psychology and Psychiatry, and Allied Disciplines 42 (3): 299–307. March 2001. doi:10.1111/1469-7610.00723. ISSN 0021-9630. OCLC 01307942. PMID 11321199.
46. ↑ "The relationship between restrictive and repetitive behaviors in individuals with autism and obsessive compulsive symptoms in parents". Child Psychiatry and Human Development 36 (2): 155–65. 2005. doi:10.1007/s10578-005-2973-7. PMID 16228144.
47. ↑ "Intergenerational transmission of subthreshold autistic traits in the general population". Biological Psychiatry 57 (6): 655–60. March 2005. doi:10.1016/j.biopsych.2004.12.014. PMID 15780853.
48. ↑ "A family history study of Asperger syndrome". Journal of Autism and Developmental Disorders 35 (2): 177–82. April 2005. doi:10.1007/s10803-004-1996-4. PMID 15909404.
49. ↑ "Half of Moms of Kids With Autism Have High Depressive Symptoms". August 26, 2022. https://neurosciencenews.com/depression-asd-moms-21298/.
50. ↑ "Excess of twins among affected sibling pairs with autism: implications for the etiology of autism". American Journal of Human Genetics 69 (5): 1062–7. November 2001. doi:10.1086/324191. PMID 11590546.
51. ↑ 51.0 51.1 51.2 51.3 51.4 "On the twin risk in autism". American Journal of Human Genetics 71 (4): 941–6. October 2002. doi:10.1086/342990. PMID 12297988.
52. ↑ "The contribution of de novo coding mutations to autism spectrum disorder". Nature 515 (7526): 216–21. November 2014. doi:10.1038/nature13908. PMID 25363768. Bibcode: 2014Natur.515..216I.
53. ↑ "Mechanisms for differences in monozygous twins". Early Human Development 64 (2): 105–17. September 2001. doi:10.1016/S0378-3782(01)00171-2. PMID 11440823.
54. ↑ 54.0 54.1 54.2 "From de novo mutations to personalized therapeutic interventions in autism". Annual Review of Medicine 66 (1): 487–507. 14 January 2015. doi:10.1146/annurev-med-091113-024550. PMID 25587659.
55. ↑ "The role of de novo mutations in the genetics of autism spectrum disorders". Nature Reviews. Genetics 15 (2): 133–41. February 2014. doi:10.1038/nrg3585. PMID 24430941.
56. ↑ "SFARI CNV". https://gene.sfari.org/autdb/CNVHome.do.
57. ↑ "SFARI gene scoring module". https://gene.sfari.org/autdb/GS_Home.do.
58. ↑ 58.0 58.1 "The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders". The Journal of Clinical Investigation 119 (4): 747–54. April 2009. doi:10.1172/JCI37934. PMID 19339766.
59. ↑ 59.0 59.1 "Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size". Journal of Medical Genetics 47 (5): 332–41. May 2010. doi:10.1136/jmg.2009.073015. PMID 19914906.
60. ↑ 60.0 60.1 "Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence". The Lancet. Neurology 12 (4): 406–14. April 2013. doi:10.1016/S1474-4422(13)70011-5. PMID 23518333.
61. ↑ "Microduplications of 16p11.2 are associated with schizophrenia". Nature Genetics 41 (11): 1223–7. November 2009. doi:10.1038/ng.474. PMID 19855392.
62. ↑ The Simons Vip Consortium (March 2012). "Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders". Neuron 73 (6): 1063–7. doi:10.1016/j.neuron.2012.02.014. PMID 22445335.
63. ↑ "CNVs conferring risk of autism or schizophrenia affect cognition in controls". Nature 505 (7483): 361–6. January 2014. doi:10.1038/Nature12818. PMID 24352232. Bibcode: 2014Natur.505..361S. http://www.hirsla.lsh.is/lsh/handle/2336/311615.
64. ↑ 64.0 64.1 "A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism". Translational Psychiatry 4 (1): e354. January 2014. doi:10.1038/tp.2013.124. PMID 24473445.
65. ↑ "A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A". American Journal of Medical Genetics. Part A 131 (1): 1–10. November 2004. doi:10.1002/ajmg.a.30297. PMID 15389703.
66. ↑ "Epigenetics of autism spectrum disorders". Human Molecular Genetics 15 (Review 2): R138-50. October 2006. doi:10.1093/hmg/ddl213. PMID 16987877. http://hmg.oxfordjournals.org/cgi/content/full/15/suppl_2/R138.
67. ↑ "Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism". Pediatric Research 47 (1): 9–16. January 2000. doi:10.1203/00006450-200001000-00006. PMID 10625077.
68. ↑ "Psychosis and autism as diametrical disorders of the social brain". The Behavioral and Brain Sciences 31 (3): 241–61; discussion 261–320. June 2008. doi:10.1017/S0140525X08004214. PMID 18578904. http://eprints.lse.ac.uk/21571/1/Psychosis and autism as diametrical disorders of the social brain (LSERO).pdf.
69. ↑ "Etiology of infantile autism: a review of recent advances in genetic and neurobiological research". Journal of Psychiatry & Neuroscience 24 (2): 103–15. March 1999. PMID 10212552.
70. ↑ "The teratology of autism". International Journal of Developmental Neuroscience 23 (2–3): 189–99. 2005. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.
71. ↑ "Incidence of autism spectrum disorders: changes over time and their meaning". Acta Paediatrica 94 (1): 2–15. January 2005. doi:10.1111/j.1651-2227.2005.tb01779.x. PMID 15858952.
72. ↑ "Tracing the origins of autism: a spectrum of new studies". Environmental Health Perspectives 114 (7): A412-8. July 2006. doi:10.1289/ehp.114-a412. PMID 16835042. PMC 1513312. http://www.ehponline.org/members/2006/114-7/focus.html.
73. ↑ 73.0 73.1 73.2 73.3 73.4 73.5 73.6 73.7 "Gene linked to sex differences in autism" (in EN). NIH Research Matters (U.S. Department of Health and Human Services). 2020-04-13. https://www.nih.gov/news-events/nih-research-matters/gene-linked-sex-differences-autism. Retrieved 2022-02-28.
74. ↑ 74.0 74.1 Loomes, Rachel; Hull, Laura; Mandy, William Polmear Locke (2017-04-06). "What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis". Journal of the American Academy of Child and Adolescent Psychiatry 56 (6): 466–474. doi:10.1016/j.jaac.2017.03.013. ISSN 1527-5418. PMID 28545751. https://pubmed.ncbi.nlm.nih.gov/28545751/.
75. ↑ Zhao, Xiaoyue; Leotta, Anthony; Kustanovich, Vlad; Lajonchere, Clara; Geschwind, Daniel H.; Law, Kiely; Law, Paul; Qiu, Shanping et al. (2007-07-31). "A unified genetic theory for sporadic and inherited autism". Proceedings of the National Academy of Sciences of the United States of America 104 (31): 12831–12836. doi:10.1073/pnas.0705803104. ISSN 0027-8424. PMID 17652511. Bibcode: 2007PNAS..10412831Z.
76. ↑ 76.0 76.1 76.2 76.3 76.4 Nguyen, Thien A.; Wu, Kunwei; Pandey, Saurabh; Lehr, Alexander W.; Li, Yan; Bemben, Michael A.; Badger, John D.; Lauzon, Julie L. et al. (2020-06-03). "A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y". Neuron 106 (5): 759–768.e7. doi:10.1016/j.neuron.2020.03.008. ISSN 1097-4199. PMID 32243781.
77. ↑ 77.0 77.1 77.2 Jamain, Stéphane; Quach, Hélène; Betancur, Catalina; Råstam, Maria; Colineaux, Catherine; Gillberg, I Carina; Söderström, Henrik; Giros, Bruno et al. (2020-03-30). "Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism". Nature Genetics 34 (1): 27–29. doi:10.1038/ng1136. ISSN 1061-4036. PMID 12669065.
78. ↑ "Recent advances in the pathogenesis of syndromic autisms". International Journal of Pediatrics 2009: 198736. 2009. doi:10.1155/2009/198736. PMID 19946417.
79. ↑ "Comparative analysis of neurological disorders focuses genome-wide search for autism genes". Genomics 93 (2): 120–9. February 2009. doi:10.1016/j.ygeno.2008.09.015. PMID 18950700.
80. ↑ "Common genetic variants on 5p14.1 associate with autism spectrum disorders". Nature 459 (7246): 528–33. May 2009. doi:10.1038/nature07999. PMID 19404256. Bibcode: 2009Natur.459..528W.
81. ↑ "Association between microdeletion and microduplication at 16p11.2 and autism". The New England Journal of Medicine 358 (7): 667–75. February 2008. doi:10.1056/NEJMoa075974. PMID 18184952.
82. ↑ "Structural variation of chromosomes in autism spectrum disorder". American Journal of Human Genetics 82 (2): 477–88. February 2008. doi:10.1016/j.ajhg.2007.12.009. PMID 18252227. PMC 2426913. http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00035-3.
83. ↑ "MAP'ing CNS development and cognition: an ERKsome process". Neuron 61 (2): 160–7. January 2009. doi:10.1016/j.neuron.2009.01.001. PMID 19186160.
84. ↑ "Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus". American Journal of Human Genetics 77 (5): 851–68. November 2005. doi:10.1086/497705. PMID 16252243.
85. ↑ "No association between the EN2 gene and autistic disorder". Journal of Medical Genetics 40 (1): 4e–4. January 2003. doi:10.1136/jmg.40.1.e4. PMID 12525552.
86. ↑ "Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism". Biological Psychiatry 55 (4): 413–9. February 2004. doi:10.1016/j.biopsych.2003.10.005. PMID 14960295.
87. ↑ "No association between allelic variants of HOXA1/HOXB1 and autism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 124B (1): 64–7. January 2004. doi:10.1002/ajmg.b.20094. PMID 14681917.
88. ↑ "The HOXA1 A218G polymorphism and autism: lack of association in white and black patients from the South Carolina Autism Project". Journal of Autism and Developmental Disorders 33 (3): 343–8. June 2003. doi:10.1023/A:1024414803151. PMID 12908836.
89. ↑ "No association between HOXA1 and HOXB1 genes and autism spectrum disorders (ASD)". Journal of Medical Genetics 39 (11): 70e–70. November 2002. doi:10.1136/jmg.39.11.e70. PMID 12414832.
90. ↑ "Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development". Nature Genetics 37 (10): 1035–7. October 2005. doi:10.1038/ng1636. PMID 16155570.
91. ↑ "Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders". Teratology 62 (6): 393–405. December 2000. doi:10.1002/1096-9926(200012)62:6<393::AID-TERA6>3.0.CO;2-V. PMID 11091361.
92. ↑ "Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development". Development 126 (22): 5027–40. November 1999. doi:10.1242/dev.126.22.5027. PMID 10529420.
93. ↑ "In utero exposure to valproic acid and autism--a current review of clinical and animal studies". Neurotoxicology and Teratology 36: 47–56. 2013. doi:10.1016/j.ntt.2013.01.004. PMID 23395807.
94. ↑ "Haplotypes in the gene encoding protein kinase c-beta (PRKCB1) on chromosome 16 are associated with autism". Molecular Psychiatry 10 (10): 950–60. October 2005. doi:10.1038/sj.mp.4001704. PMID 16027742.
95. ↑ "Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling". Molecular Psychiatry 24 (9): 1329–1350. September 2019. doi:10.1038/s41380-018-0025-5. PMID 29467497.
96. ↑ 96.0 96.1 "The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13". Neurobiology of Disease 38 (2): 181–91. May 2010. doi:10.1016/j.nbd.2008.08.011. PMID 18840528.
97. ↑ "The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells". The Journal of Cell Biology 167 (5): 945–52. December 2004. doi:10.1083/jcb.200404108. PMID 15569713.
98. ↑ 98.0 98.1 98.2 "Deletion 22q13 Syndrome". Ophanet.com. 2003. http://www.orpha.net/data/patho/GB/uk-22q13.pdf.
99. ↑ 99.0 99.1 "Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders". Nature Genetics 39 (1): 25–7. January 2007. doi:10.1038/ng1933. PMID 17173049.
100. ↑ "Neuroligins". Cell adhesion at synapses Synapse Web, Laboratory of Synapse Structure and Function. Human Brain Project. National Institute of Mental Health and the National Institute of Drug Abuse. 2001. http://synapse-web.org/lab/harris/Lecture10-11/sld069.htm.
101. ↑ "Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins". Cell 119 (7): 1013–26. December 2004. doi:10.1016/j.cell.2004.11.035. PMID 15620359.
102. ↑ "A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice". Science 318 (5847): 71–6. October 2007. doi:10.1126/science.1146221. PMID 17823315. Bibcode: 2007Sci...318...71T.
103. ↑ "No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B (4): 535–7. June 2008. doi:10.1002/ajmg.b.30618. PMID 18189281.
104. ↑ 104.0 104.1 "Gene Linked to Autism in Families with More Than One Affected Child". National Institutes of Health News. U.S. Department of Health and Human Services. 17 October 2006. http://www.nih.gov/news/pr/oct2006/nimh-17.htm.
105. ↑ "A genetic variant that disrupts MET transcription is associated with autism". Proceedings of the National Academy of Sciences of the United States of America 103 (45): 16834–9. November 2006. doi:10.1073/pnas.0605296103. PMID 17053076.
106. ↑ "Disruption of neurexin 1 associated with autism spectrum disorder". American Journal of Human Genetics 82 (1): 199–207. January 2008. doi:10.1016/j.ajhg.2007.09.011. PMID 18179900. PMC 2253961. http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00017-1.
107. ↑ "Frequency and Complexity of De Novo Structural Mutation in Autism". American Journal of Human Genetics 98 (4): 667–79. April 2016. doi:10.1016/j.ajhg.2016.02.018. PMID 27018473.
108. ↑ "Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene". American Journal of Human Genetics 82 (1): 150–9. January 2008. doi:10.1016/j.ajhg.2007.09.005. PMID 18179893. PMC 2253955. http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00011-0.
109. ↑ "A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism". American Journal of Human Genetics 82 (1): 160–4. January 2008. doi:10.1016/j.ajhg.2007.09.015. PMID 18179894. PMC 2253968. http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00021-3.
110. ↑ "Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders". American Journal of Human Genetics 82 (1): 165–73. January 2008. doi:10.1016/j.ajhg.2007.09.017. PMID 18179895. PMC 2253974. http://www.ajhg.org/AJHG/fulltext/S0002-9297(07)00023-7.
111. ↑ "Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype". Archives of Pediatrics & Adolescent Medicine 161 (4): 356–61. April 2007. doi:10.1001/archpedi.161.4.356. PMID 17404132. http://archpedi.ama-assn.org/cgi/content/full/161/4/356.
112. ↑ "The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis". Molecular Psychiatry 20 (5): 640–6. May 2015. doi:10.1038/mp.2014.77. PMID 25092245.
113. ↑ 113.0 113.1 "Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families". Annals of Neurology 59 (1): 145–55. January 2006. doi:10.1002/ana.20722. PMID 16288458.
114. ↑ "A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands". Molecular Psychiatry 11 (1): 37–46. January 2006. doi:10.1038/sj.mp.4001754. PMID 16205737.
115. ↑ "A heterogeneity-based genome search meta-analysis for autism-spectrum disorders". Molecular Psychiatry 11 (1): 29–36. January 2006. doi:10.1038/sj.mp.4001750. PMID 16189507.
116. ↑ "A genomewide screen of 345 families for autism-susceptibility loci". American Journal of Human Genetics 73 (4): 886–97. October 2003. doi:10.1086/378778. PMID 13680528.
117. ↑ "Replication of autism linkage: fine-mapping peak at 17q21". American Journal of Human Genetics 76 (6): 1050–6. June 2005. doi:10.1086/430278. PMID 15877280.
118. ↑ "Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations". Journal of Medical Genetics 42 (4): 318–21. April 2005. doi:10.1136/jmg.2004.024646. PMID 15805158.
119. ↑ "Same DNA deletion paves paths to autism, schizophrenia" (in en-US). Spectrum. 2016-10-18. https://spectrumnews.org/opinion/viewpoint/dna-deletion-paves-paths-autism-schizophrenia/.
120. ↑ "Identifying autism loci and genes by tracing recent shared ancestry". Science 321 (5886): 218–23. July 2008. doi:10.1126/science.1157657. PMID 18621663. Bibcode: 2008Sci...321..218M.
121. ↑ "Autism: Family connections". Nature 454 (7206): 838–9. August 2008. doi:10.1038/454838a. PMID 18704077. Bibcode: 2008Natur.454..838G.
122. ↑ "Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number". Science 311 (5763): 1008–12. February 2006. doi:10.1126/science.1122511. PMID 16484497. Bibcode: 2006Sci...311.1008F.
123. ↑ "Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo". Proceedings of the National Academy of Sciences of the United States of America 105 (27): 9397–402. July 2008. doi:10.1073/pnas.0802876105. PMID 18599437. Bibcode: 2008PNAS..105.9397L.

## Further reading

* "Autism genetics: strategies, challenges, and opportunities". Autism Research 1 (1): 4–17. February 2008. doi:10.1002/aur.3. PMID 19360646. An excellent summary of the state and possible future directions of autism genetics research as of late 2007.
* "Syndromes and epistemology II: is autism a polygenic disorder?". American Journal of Medical Genetics. Part A 146A (17): 2203–12. September 2008. doi:10.1002/ajmg.a.32438. PMID 18666231. Advocates common disease rare allele (CDRA) over polygenic approaches.
* "Current developments in the genetics of autism: from phenome to genome". Journal of Neuropathology & Experimental Neurology 67 (9): 829–37. September 2008. doi:10.1097/NEN.0b013e318184482d. ISSN 0022-3069. OCLC 771166656. PMID 18716561. Focuses on attempts to match genes to behavior.

## External links

* Autism Genetic Resource Exchange (AGRE) – 'the world's first collaborative gene bank for autism'

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Pervasive developmental disorders and autism spectrum (F84, 299)

Main|

* Causes
* Comorbid conditions
* Epidemiology
* Heritability
* Societal and cultural aspects
* Medical model
* Therapies

Diagnoses|

* Autism spectrum (High-functioning autism
* Classic Autism
* Asperger syndrome
* Pervasive developmental disorder not otherwise specified
* Childhood disintegrative disorder
* Rett syndrome)

Related conditions|

* Alexithymia
* Attention deficit hyperactivity disorder
* Anxiety disorder (obsessive–compulsive disorder)
* Late talker
* Epilepsy
* Fragile X syndrome
* Hyperlexia
* Savant syndrome
* Sensory processing disorder
* Intellectual disability
* Developmental coordination disorder
* Multiple complex developmental disorder

Controversies|

* Autism rights movement
* Autistic enterocolitis
* Facilitated communication
* MMR vaccine
* Rapid prompting method
* Thiomersal (Chelation)

Diagnostic scales|

* Gilliam Asperger's disorder scale
* Autism Diagnostic Observation Schedule
* Autism Diagnostic Interview
* Autism-spectrum quotient
* Childhood Autism Rating Scale

Lists|

* Autism-related topics
* Fictional characters
* Schools

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