Heritability of autism
Encyclopedia
The heritability of autism is the proportion 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 is complex and it is unclear whether autism spectrum disorder (ASD) is explained more by multigene interactions or by rare mutation
s with major effects. Early studies of twins
estimated the heritability of autism to be more than 90%; in other words, that 90% of the differences between autistic and non-autistic individuals is due to genetic effects. This may be an overestimate; new twin data and models with structural genetic variation are needed. When only one identical twin is autistic, the other often has learning or social disabilities. For adult siblings, the risk of having one or more features of the broader autism phenotype
might be as high as 30%, much higher than the risk in controls.
Genetic linkage
analysis has been inconclusive; many association analyses
have had inadequate power. For each autistic individual, mutation
s in more than one gene may be 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. However, for most of the candidate genes, the actual mutations that increase the risk 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
.
The large number of autistic individuals with unaffected family members may result from copy number variations (CNVs)—spontaneous alterations in the genetic material during meiosis
that delete or duplicate
genetic material. Sporadic (non-inherited) cases have been examined to identify candidate genetic loci
involved in autism. Using array comparative genomic hybridization
(array CGH), a technique for detecting CNVs, one study found them in 10% of families with one affected child. Some of the altered loci had been identified in previous studies of inherited autism; many were unique to the sporadic cases examined in this study. Hence, 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.
Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array CGH improves, 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. 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. It may be that using autism-related subphenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci.
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. 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.
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. 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 and 11 MZ pairs 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.
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 suffered infrequent seizures, remained autistic. The report noted that genetic factors were not "all important" in the development of the twins.
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.
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.
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."
A 1999 study looked at social cognitive skills in general-population children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.
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.
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
.
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."
An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.
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.
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.
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."
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."
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.
A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.
Autism was found to occur more often in families of physicists, engineers and scientists. Other studies have yielded similar results. Findings of this nature have led to the coinage of the term "geek syndrome".
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.
A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents. Another 2005 study focused on sub-threashold 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.
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.
in the development of autism, presumably due to perinatal factors. However, three large-scale epidemiological studies have refuted this idea.
Some researchers have speculated that what we currently refer to as "autism" may be a catch-all description for many yet unknown conditions with different genetic and/or environmental etiologies. This would appear to make the effort to find a genotype
model a lot more difficult, and perhaps even pointless. Nevertheless, a number of genetic models have been proposed to try to explain the results of twin and sibling studies.
and 22q13 deletion syndrome
. These syndromes are associated with different gene mutations and, it is assumed, different mechanisms.
formation. For example, one model is that many mutations converge on disruption of ERK
and PI3K signaling, which in turn affect MET
and other receptor tyrosine kinase
s.
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.
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.
, strong evidence that autism arises very early in development. Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies, extensive searches are underway.
s 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 genotype
s 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.
-wide scans have been performed identifying markers across many chromosome
s.
A few examples of loci that have been studied are the 17q21 region, the 3p24-26 locus, PTEN, and 15q11.2–q13.
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
, one of the transcription factors known to be regulated by neuronal activity and that itself has also recently been implicated as an autism-related disorder candidate gene.
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
that can be explained by genetic variation
Genetic variation
Genetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection. Genetic variation is brought about by mutation, a change in a chemical structure of a gene. Polyploidy is an...
; if the heritability
Heritability
The Heritability of a population is the proportion of observable differences between individuals that is due to genetic differences. Factors including genetics, environment and random chance can all contribute to the variation between individuals in their observable characteristics...
of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis, although the genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
of autism is complex and it is unclear whether autism spectrum disorder (ASD) is explained more by multigene interactions or by rare mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s with major effects. Early studies of twins
Twin study
Twin studies help disentangle the relative importance of environmental and genetic influences on individual traits and behaviors. Twin research is considered a key tool in behavioral genetics and related fields...
estimated the heritability of autism to be more than 90%; in other words, that 90% of the differences between autistic and non-autistic individuals is due to genetic effects. This may be an overestimate; new twin data and models with structural genetic variation are needed. When only one identical twin is autistic, the other often has learning or social disabilities. For adult siblings, the risk of having one or more features of the broader autism phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
might be as high as 30%, much higher than the risk in controls.
Genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
analysis has been inconclusive; many association analyses
Genetic association
Genetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic....
have had inadequate power. For each autistic individual, mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in more than one gene may be 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
Neural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...
and function. However, for most of the candidate genes, the actual mutations that increase the risk for autism have not been identified. Typically, autism cannot be traced to a Mendelian (single-gene) mutation or to single chromosome abnormalities
Chromosome abnormalities
A chromosome anomaly, abnormality or aberration reflects an atypical number of chromosomes or a structural abnormality in one or more chromosomes. A Karyotype refers to a full set of chromosomes from an individual which can be compared to a "normal" Karyotype for the species via genetic testing. A...
such as fragile X syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
or 22q13 deletion syndrome
22q13 deletion syndrome
22q13 Deletion Syndrome , also known as Phelan-McDermid Syndrome, is a genetic disorder caused by a microdeletion on chromosome 22. The deletion occurs at the terminal end of the chromosome at the location designated q13.3...
.
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
that delete or duplicate
Gene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...
genetic material. Sporadic (non-inherited) cases have been examined to identify candidate genetic loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
involved in autism. Using array comparative genomic hybridization
Array comparative genomic hybridization
Array-comparative genomic hybridization is a technique to detect genomic copy number variations at a higher resolution level than chromosome-based comparative genomic hybridization .-Process:DNA from...
(array CGH), a technique for detecting CNVs, one study found them in 10% of families with one affected child. Some of the altered loci had been identified in previous studies of inherited autism; many were unique to the sporadic cases examined in this study. Hence, 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.
Although the fraction of autism traceable to a genetic cause may grow to 30–40% as the resolution of array CGH improves, 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. The Autism Genome Project database contains genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
and CNV data that connect autism to genetic loci and suggest that every human chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
may be involved. It may be that using autism-related subphenotypes instead of the diagnosis of autism per se may be more useful in identifying susceptible loci.
Twin studies
Twin studies are a helpful tool in determining the heritabilityHeritability
The Heritability of a population is the proportion of observable differences between individuals that is due to genetic differences. Factors including genetics, environment and random chance can all contribute to the variation between individuals in their observable characteristics...
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
Assortative mating
Assortative mating , and the related concept Disassortative mating, is the phenomenon where a sexually reproducing organism chooses to mate with individuals that are similar or dissimilar to itself in some specific manner...
.
An example of a condition that appears to have very little if any genetic influence is irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
(IBS), with a concordance of 28% vs. 27% for MZ and DZ pairs respectively. An
example of a human characteristics that is extremely heritable is eye color
Eye color
Eye color is a polygenic phenotypic character and is determined by two distinct factors: the pigmentation of the eye's iris and the frequency-dependence of the scattering of light by the turbid medium in the stroma of the iris....
, with a concordance of 98% for MZ pairs and 7–49% for DZ pairs depending on age.
Identical twin studies put autism's heritability
Heritability
The Heritability of a population is the proportion of observable differences between individuals that is due to genetic differences. Factors including genetics, environment and random chance can all contribute to the variation between individuals in their observable characteristics...
in a range between 36% and 95.7%, with concordance for a broader phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
usually found at the higher end of the range. 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 and 11 MZ pairs 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.
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 suffered infrequent seizures, remained autistic. The report noted that genetic factors were not "all important" in the development of the twins.
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.
In a 1989 study, Nordic countries
Nordic countries
The Nordic countries make up a region in Northern Europe and the North Atlantic which consists of Denmark, Finland, Iceland, Norway and Sweden and their associated territories, the Faroe Islands, Greenland and Åland...
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.
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."
A 1999 study looked at social cognitive skills in general-population children and adolescents. It found "poorer social cognition in males", and a heritability of 0.68 with higher genetic influence in younger twins.
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.
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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
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."
An English twin study in 2006 found high heritability for autistic traits in a large group of 3,400 pairs of twins.
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.
Sibling studies
The importance of sibling studies lies in contrasting their results to those of fraternal (DZ) twin studies, plus their sample sizes can be much larger. Environment sharing by siblings is presumably different enough to that of DZ twins to shed some light on the magnitude of environmental influence. This should even be true to some extent regarding the prenatal environment. Unfortunately DZ twin study findings have yielded a very large range of variance and are error prone because of the apparent low concordance and the fact that they typically look at a small number of DZ pairs. For example, in studies involving 10 DZ pairs, a concordance below 10% would be impossible to determine precisely.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.
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."
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
Asperger syndrome
Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development...
or PDD
PDD
PDD is an abbreviation for pervasive developmental disorder.PDD may also refer to:* P. Diddy* Partnership for Democracy and Development in Central America* Pas de deux, a type of ballet dance...
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."
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.
Other family studies
A 1994 study looked at the personalities of parents of autistic children, using parents of children with Down's syndrome as controls. Using standardized tests it was found that parents of autistic children were "more aloof, untactful and unresponsive."A 1997 study found higher rates of social and communication deficits and stereotyped behaviors in families with multiple-incidence autism.
Autism was found to occur more often in families of physicists, engineers and scientists. Other studies have yielded similar results. Findings of this nature have led to the coinage of the term "geek syndrome".
A 2001 study of brothers and parents of autistic boys looked into the phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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.
A study in 2005 showed a positive correlation between repetitive behaviors in autistic individuals and obsessive-compulsive behaviors in parents. Another 2005 study focused on sub-threashold 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.
A 2005 report examined the family psychiatric history of 58 subjects with Asperger syndrome
Asperger syndrome
Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development...
(AS) diagnosed according to DSM-IV criteria. Three (5%) had first-degree relatives with AS. Nine (19%) had a family history of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Thirty five (60%) had a family history of depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
. Out of 64 siblings, 4 (6.25%) were diagnosed with AS.
Twinning risk
It has been suggested that the twinning process itself is a risk factorin the development of autism, presumably due to perinatal factors. However, three large-scale epidemiological studies have refuted this idea.
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 mental retardation a characteristic of the genotypeGenotypeThe genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
or something totally independent?
Some researchers have speculated that what we currently refer to as "autism" may be a catch-all description for many yet unknown conditions with different genetic and/or environmental etiologies. This would appear to make the effort to find a genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
model a lot more difficult, and perhaps even pointless. Nevertheless, a number of genetic models have been proposed to try to explain the results of twin and sibling studies.
Single genes
Autism sometimes arises from rare single-gene neurodevelopmental disorders such as fragile X syndromeFragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
and 22q13 deletion syndrome
22q13 deletion syndrome
22q13 Deletion Syndrome , also known as Phelan-McDermid Syndrome, is a genetic disorder caused by a microdeletion on chromosome 22. The deletion occurs at the terminal end of the chromosome at the location designated q13.3...
. These syndromes are associated with different gene mutations and, it is assumed, different mechanisms.
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, affect key developmental processes such as synapseSynapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
formation. For example, one model is that many mutations converge on disruption of ERK
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
and PI3K signaling, which in turn affect MET
C-MET
c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity...
and other receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s.
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 mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
with poor penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
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.
Epigenetic
Several epigenetic models of autism have been proposed. 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 regulatory factors. An epigenetic model would help explain why standard genetic screening strategies have so much difficulty with autism.Genomic imprinting
Genomic imprinting models have been proposed; one of their strengths is explaining the high male-to-female ratio in ASD. One hypothesis is that autism is in some sense diametrically opposite to schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
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.
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. 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 conceptionHuman fertilization
Human fertilization is the union of a humanoid egg and sperm, usually occurring in the ampulla of the uterine tube. The result of this union is the production of a zygote, or fertilized egg, initiating prenatal development...
, strong evidence that autism arises very early in development. Although evidence for other environmental causes is anecdotal and has not been confirmed by reliable studies, extensive searches are underway.
Candidate gene loci
Known genetic syndromes, mutations, and metabolic diseases account for up to 20% of autism cases. A number of alleleAllele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s have been shown to have strong linkage to the autism phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. 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 genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
s that are
manifested as the autism phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. 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.
Primary
| Gene | OMIM/# | Locus Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map... |
Description >- | CDH9 CDH9 Cadherin 9 is a protein that in humans is encoded by the CDH9 gene.... , CDH10 CDH10 Cadherin 10 is a protein that in humans is encoded by the CDH10 gene.... |
5p14.1 | >- | 16p11.2 | mitogen-activated protein kinase Mitogen-activated protein kinase Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated... s 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 Neuro-cardio-facial-cutaneous syndromes Neuro-cardio-facial-cutaneous-syndromes , is a group of developmental disorders with a genetic ground, affecting the nervous system, circulatory system, facial and cutaneous development... (NCFC), which are characterized by cranio-facial development disturbances that also can be found in some cases of autism. >- | SERT (SLC6A4) |
17q11.2 | depression Clinical depression Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities... but only as a result of social adversity, although other studies have found no link. Significant linkage in families with only affected males has been shown. Researchers have also suggested that the gene contributes to hyperserotonemia Serotonin syndrome Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs... . However, a 2008 meta-analysis of family- and population-based studies found no significant overall association between autism and either the promoter insertion/deletion (5-HTTLPR 5-HTTLPR 5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.Since the polymorphism was identified in the middle of the 1990s,... ) or the intron 2 VNTR (STin2 VNTR) polymorphisms. >- | CACNA1G CACNA1G Calcium channel, voltage-dependent, T type, alpha 1G subunit, also known as CACNA1G or Cav3.1 is a protein which in humans is encoded by the CACNA1G gene.- Function :... |
17q21.33 | >- | multiple | GABA Gabâ Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions... is the primary inhibitory neurotransmitter Neurotransmitter Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to... of the human brain. Ma et al. (2005) concluded that GABRA4 GABRA4 Gamma-aminobutyric acid receptor subunit alpha-4 is a protein that in humans is encoded by the GABRA4 gene.... is involved in the etiology of autism, and that it potentially increases autism risk through interaction with GABRB1. The GABRB3 GABRB3 Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the GABRB3 gene.... gene has been associated with savant Savant syndrome Savant syndrome , sometimes referred to as savantism, is a rare condition in which people with developmental disorders have one or more areas of expertise, ability, or brilliance that are in contrast with the individual's overall limitations... skills. The GABRB3 gene deficient mouse has been proposed as a model of ASD. >- | Engrailed 2 (EN2) |
7q36.2 | cerebellar Cerebellum The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established... 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. But at least one study has found no association. >- | ? |
3q25-27 | Asperger syndrome Asperger syndrome Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development... with this locus. The most prominent markers are in the vicinity of D3S3715 and D3S3037. >- | Reelin Reelin Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the... |
7q21-q36 | Reelin Reelin Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the... glycoprotein Glycoprotein Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending... is believed to be involved in memory formation, neurotransmission, and synaptic plasticity. A number of studies have shown an association between the REELIN gene and autism, but a couple of studies were unable to duplicate linkage findings. >- | SLC25A12 SLC25A12 Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene.-Further reading:... |
2q31 | >- | multiple | 16p11.2 | et al. (2005) found a strong association between this gene and autism. This is a recent finding that needs to be replicated. >- | FOXP2 FOXP2 Forkhead box protein P2 also known as FOXP2 is a protein that in humans is encoded by the FOXP2 gene, located on human chromosome 7 . FOXP2 orthologs have also been identified in all mammals for which complete genome data are available... |
7q31 | , AUTSX3 | 15q11.2–q13 | Angelman syndrome Angelman syndrome Angelman syndrome is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements , frequent laughter or smiling, and usually a happy demeanor.... . MeCP2 deficiency results in reduced expression of UBE3A in some studies. >- | Shank3 SHANK3 SH3 and multiple ankyrin repeat domains 3, also known as SHANK3, is a human gene on chromosome 22.This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane... (ProSAP2) |
22q13 | SHANK3 SHANK3 SH3 and multiple ankyrin repeat domains 3, also known as SHANK3, is a human gene on chromosome 22.This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane... (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. SHANK3 is also a binding partner of chromosome 22q13 (i.e. a specific section of Chromosome 22) and neuroligin Neuroligin 300px|thumb|right|alt = Colored dice with checkered background|Tertiary structure of Neuroligin 4.Neuroligin , a type I membrane protein, is a protein on the postsynaptic membrane that mediates synapse formation between neurons. Neuroligins mediate signaling across the synapse and affect the... 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. 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 Haploinsufficiency Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state... ) 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. A deletion of a single copy of a gene on chromosome 22q13 Chromosome 22 (human) Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of Chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and representing between 1.5 and 2 % of the total DNA in cells.In 1999,... 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 (see also 22q13 deletion syndrome 22q13 deletion syndrome 22q13 Deletion Syndrome , also known as Phelan-McDermid Syndrome, is a genetic disorder caused by a microdeletion on chromosome 22. The deletion occurs at the terminal end of the chromosome at the location designated q13.3... ). 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. >- | NLGN3 NLGN3 Neuroligin-3 is a protein that in humans is encoded by the NLGN3 gene.-Further reading:... |
, AUTSX1 | Xq13 | protein Protein Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of... (homologous to acetylcholinesterase Acetylcholinesterase "Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate... and other esterases) that binds to synaptic membranes. Neuroligins organize postsynaptic membranes that function to transmit nerve cell messages (excitatory) and stop those transmissions (inhibitory); 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. Though not present in all individuals with autism, these mutations hold potential to illustrate some of the genetic components of spectrum disorders. However, a 2008 study found no evidence for involvement of neuroligin-3 and neuroligin-4x with high-functioning ASD. >- | MET C-MET c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity... |
7q31 | tyrosine kinase Tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions.... gene Gene A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains... ) linked to brain Brain The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,... development, regulation of the immune system Immune system An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own... , and repair of the gastrointestinal system, has been linked to autism. This MET gene codes for a protein Protein Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of... that relays signals that turn on a cell’s internal machinery. Impairing the receptor’s signaling interferes with neuron Neuron A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous... migration and disrupts neuronal growth in the cerebral cortex Cerebral cortex The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different... and similarly shrinks the cerebellum Cerebellum The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established... —abnormalities also seen in autism. It is also known to play a key role in both normal and abnormal development, such as cancer Cancer Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the... metastases (hence the name MET). A mutation of the gene, rendering it less active, has been found to be common amongst children with autism. Mutation in the MET gene demonstrably raises risk of autism by 2.27 times. >- | neurexin 1 |
2q32 | DNA DNA Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in... from 1,181 families in what was the largest-scale genome scan conducted in autism research at the time. The objective of the study was to locate specific brain cells involved in autism to find regions in the genome Genome In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA.... linked to autism susceptibility genes Gênes Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and... . 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 actually locating yet 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. >- | CNTNAP2 CNTNAP2 Contactin-associated protein-like 2 is a protein that in humans is encoded by the CNTNAP2 gene.This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal... |
7q35-q36 | CNTNAP2 CNTNAP2 Contactin-associated protein-like 2 is a protein that in humans is encoded by the CNTNAP2 gene.This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal... gene, a member of the neurexin superfamily, that implicate it as contributing to autism. >- | GSTP1 GSTP1 Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.-Interactions:GSTP1 has been shown to interact with Fanconi anemia, complementation group C and MAPK8.-Further reading:... |
11q13 | glutathione Glutathione Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain... S-transferase Transferase In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule to another . For example, an enzyme that catalyzed this reaction would be a transferase:In this example, A would be the donor, and B would be the acceptor... P1 gene (GSTP1 GSTP1 Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.-Interactions:GSTP1 has been shown to interact with Fanconi anemia, complementation group C and MAPK8.-Further reading:... ) acts in the mother during pregnancy and increases the likelihood of autism in the child. >- | PRL, PRLR, OXTR |
multiple | A 2008 study found preliminary data supporting the hypothesis that ASD is associated with allelic variants of genes needed for typical affiliative behaviors. The strongest results were obtained for the PRL, PRLR, and OXTR genes. |
Others
There is a large number of other candidate loci which either should be looked at or have been shown to be promising. Several genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
-wide scans have been performed identifying markers across many chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s.
A few examples of loci that have been studied are the 17q21 region, the 3p24-26 locus, PTEN, and 15q11.2–q13.
Homozygosity mapping in pedigrees with shared ancestry and autism incidence has recently implicated the following candidate genes: PCDH10
PCDH10
Protocadherin-10 is a protein that in humans is encoded by the PCDH10 gene.-Further reading:...
, DIA1 (formerly known as C3ORF58), NHE9, CNTN3
CNTN3
Contactin-3 is a protein that in humans is encoded by the CNTN3 gene.-Further reading:...
, SCN7A
SCN7A
Sodium channel protein type 7 subunit alpha is a protein that in humans is encoded by the SCN7A gene.-See also:* Sodium channelScn7a is the name of the gene that encodes to a membrane protein, in particular a Sodium Channel Nax It belongs to a family of Sodium Channel known as Voltage-Gated, but...
, and RNF8
RNF8
E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene.-Interactions:RNF8 has been shown to interact with Retinoid X receptor alpha.-Further reading:- External links :...
. Several of these genes appeared to be targets of MEF2
Mef2
In the field of molecular biology, myocyte enhancer factor-2 proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2...
, one of the transcription factors known to be regulated by neuronal activity and that itself has also recently been implicated as an autism-related disorder candidate gene.
Further reading
An excellent summary of the state and possible future directions of autism genetics research as of late 2007. Advocates common disease rare allele (CDRA) over polygenic approaches. Focuses on attempts to match genes to behavior.External links
- Autism Genetic Resource Exchange (AGRE) - 'the world's first collaborative gene bank for autism'