Tag Archives: Genetic Basis

Question?: Rett Syndrome Treatment

Carol asks…

Pervasive Developmental Disorder…?

What is it??? What are the causes? What does it do? How to get rid of it if you can……

THANKS !
PLEASE ANSWERRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

admin answers:

Pervasive developmental disorders cause abnormal development, including social and communication development. The symptoms appear early on – by the age of 3 at least, except in one of the disorders – and last throughout the lifetime. There are five of them: autism, Asperger’s syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). Autism, Asperger’s, and PDD-NOS are called the autism spectrum.

Symptoms of autism include difficulty socializing and communicating with others, delayed speech, lack of eye contact, difficulty interpreting nonverbal signals, intense fixations and interests, repetitive or compulsive movements, poor motor coordination, and abnormal sensory processing. The severity of these symptoms varies considerably. Asperger’s syndrome is a mild and high-functioning form of autism. The symptoms are the same except there is no speech delay. PDD-NOS is when someone has some autistic traits and significant impairment, but does not meet the diagnostic criteria for another PDD. These disorders have a genetic basis, but researchers have not yet uncovered the specifics. Some people believe environmental factors also play a role.

Childhood disintegrative disorder is when a child appears to be developing normally, then suddenly regresses sometime after the age of 3. The cause of this disorder is unknown. Rett syndrome occurrs almost exclusively in females. Infants with this disorder experience regression between 6-18 months of age. Symptoms include lack of speech, seizures, sensory problems, poor motor coordination, growth abnormalities, and repetitive movements. It is caused by a gene mutation on the X chromosome.

None of the PDDs are curable. There are many treatments available, including occupational therapy, cognitive behavioral therapy, applied behavior analysis, speech therapy, social skills training, behavior therapy, and certain medications.

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Question?: Rett Syndrome Genetics

George asks…

what is autism?

Im not sure what that is

admin answers:

Autism is a brain development disorder that impairs social interaction and communication, and causes restricted and repetitive behavior, all starting before a child is three years old. This set of signs distinguishes autism from milder autism spectrum disorders (ASD) such as Asperger syndrome.[2]

Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by multigene interactions or by rare mutations.[3] In rare cases, autism is strongly associated with agents that cause birth defects.[4] Other proposed causes, such as childhood vaccines, are controversial and the vaccine hypotheses lack convincing scientific evidence.[5] Most recent reviews estimate a prevalence of one to two cases per 1,000 people for autism, and about six per 1,000 for ASD, with ASD averaging a 4.3:1 male-to-female ratio. The number of people known to have autism has increased dramatically since the 1980s, at least partly due to changes in diagnostic practice; the question of whether actual prevalence has increased is unresolved.[6]

Autism affects many parts of the brain; how this occurs is poorly understood. Parents usually notice signs in the first two years of their child’s life. Early behavioral or cognitive intervention can help children gain self-care, social, and communication skills. There is no cure.[7] Few children with autism live independently after reaching adulthood, but some become successful,[8] and an autistic culture has developed, with some seeking a cure and others believing that autism is a condition rather than a disorder.[9]
Contents
[hide]

* 1 Classification
* 2 Characteristics
o 2.1 Social development
o 2.2 Communication
o 2.3 Repetitive behavior
o 2.4 Other symptoms
* 3 Causes
* 4 Mechanism
o 4.1 Pathophysiology
o 4.2 Neuropsychology
* 5 Screening
* 6 Diagnosis
* 7 Management
* 8 Prognosis
* 9 Epidemiology
* 10 History
* 11 References
* 12 External links

Classification

Autism is a brain development disorder that first gives signs during infancy or childhood and follows a steady course without remission or relapse.[2] Impairments result from maturation-related changes in various systems of the brain.[10] Autism is one of the five pervasive developmental disorders (PDD), which are characterized by widespread abnormalities of social interactions and communication, and severely restricted interests and highly repetitive behavior.[2]
Hans Asperger introduced the modern sense of the word autism in 1938.
Hans Asperger introduced the modern sense of the word autism in 1938.[11]

Of the other four PDD forms, Asperger syndrome is closest to autism in signs and likely causes; Rett syndrome and childhood disintegrative disorder share several signs with autism, but may have unrelated causes; PDD not otherwise specified (PDD-NOS) is diagnosed when the criteria are not met for a more specific disorder.[12] Unlike autism, Asperger’s has no substantial delay in language development.[13] The terminology of autism can be bewildering, with autism, Asperger’s and PDD-NOS often called the autism spectrum disorders (ASD)[7] or sometimes the autistic disorders,[14] whereas autism itself is often called autistic disorder, childhood autism, or infantile autism. In this article, autism refers to the classic autistic disorder, while other sources sometimes use autism or the autisms to refer to ASD,[15] or equate ASD with PDD.[16] ASD, in turn, is a subset of the broader autism phenotype (BAP), which describes individuals who may not have ASD but do have autistic-like traits, such as avoiding eye contact.[17]

The manifestations of autism cover a wide spectrum, ranging from individuals with severe impairments—who may be silent, mentally disabled, and locked into hand flapping and rocking—to less impaired individuals who may have active but distinctly odd social approaches, narrowly focused interests, and verbose, pedantic communication.[18] Sometimes the syndrome is divided into low-, medium- and high-functioning autism (LFA, MFA, and HFA), based on IQ thresholds,[19] or on how much support the individual requires in daily life; these subdivisions are not standardized and are controversial. Autism can also be divided into syndromal and non-syndromal autism, where the former is associated with severe or profound mental retardation or a congenital syndrome with physical symptoms, such as tuberous sclerosis.[20] Although individuals with Asperger’s tend to perform better cognitively than those with autism, the extent of the overlap between Asperger’s, HFA, and non-syndromal autism is unclear.[21]

Some studies have reported diagnoses of autism in children due to a loss of language or social skills after 14 months of age, as opposed to a failure to make progress. Several terms are used for this phenomenon, including regressive autism, setback autism, and developmental stagnation. The validity of this distinction remains controversial; it is possible that regressive autism is a specific subtype.[22][23][24]

Characteristics

Autism is distinguished by a pattern of symptoms rather than one single symptom. The main characteristics are impairments in social interaction, impairments in communication, restricted interests and repetitive behavior. Other aspects, such as atypical eating, are also common but are not essential for diagnosis.[25] Individual symptoms of autism occur in the general population and appear not to associate highly, without a sharp line separating pathological severity from common traits.[26]

Social development

People with autism have social impairments and often lack the intuition about others that many people take for granted. Noted autistic Temple Grandin described her inability to understand the social communication of neurotypicals as leaving her feeling “like an anthropologist on Mars”.[27]

Social impairments become apparent early in childhood and continue through adulthood. Autistic infants show less attention to social stimuli, smile and look at others less often, and respond less to their own name. Autistic toddlers have more striking social deviance; for example, they have less eye contact and anticipatory postures and are more likely to communicate by manipulating another person’s hand.[24] Three- to five-year-old autistic children are less likely to exhibit social understanding, approach others spontaneously, imitate and respond to emotions, communicate nonverbally, and take turns with others. However, they do form attachments to their primary caregivers.[28] They display moderately less attachment security than usual, although this feature disappears in children with higher mental development or less severe ASD.[29] Older children and adults with ASD perform worse on tests of face and emotion recognition.[30]

Contrary to common belief, autistic children do not prefer to be alone. Making and maintaining friendships often proves to be difficult for those with autism. For them, the quality of friendships, not the number of friends, predicts how lonely they are.[31]

There are many anecdotal reports, but few systematic studies, of aggression and violence in individuals with ASD. The limited data suggest that in children with mental retardation, autism is associated with aggression, destruction of property, and tantrums. Dominick et al. Interviewed the parents of 67 children with ASD and reported that about two-thirds of the children had periods of severe tantrums and about one-third had a history of aggression, with tantrums significantly more common than in children with a history of language impairment.[32]

Communication

About a third to a half of individuals with autism do not develop enough natural speech to meet their daily communication needs.[33] Differences in communication may be present from the first year of life, and may include delayed onset of babbling, unusual gestures, diminished responsiveness, and the desynchronization of vocal patterns with the caregiver. In the second and third years, autistic children have less frequent and less diverse babbling, consonants, words, and word combinations; their gestures are less often integrated with words. Autistic children are less likely to make requests or share experiences, and are more likely to simply repeat others’ words (echolalia)[23][34] or reverse pronouns.[35] Joint attention seems to be necessary for functional speech, and deficits in joint attention seem to distinguish infants with ASD:[1] for example, they may look at a pointing hand instead of the pointed-at object,[24][34] and they consistently fail to point to “comment” about or “share” an experience at age-appropriate times.[1] Autistic children may have difficulty with imaginative play and with developing symbols into language.[23][34]

In a pair of studies, high-functioning autistic children aged 8–15 performed equally well, and adults better than individually matched controls at basic language tasks involving vocabulary and spelling. Both autistic groups performed worse than controls at complex language tasks such as figurative language, comprehension and inference. As people are often sized up initially from their basic language skills, these studies suggest that people speaking to autistic individuals are more likely to overestimate what their audience comprehends.[36]

Repetitive behavior
A young boy with autism, and the precise line of toys he made
A young boy with autism, and the precise line of toys he made

Autistic individuals display many forms of repetitive or restricted behavior, which the Repetitive Behavior Scale-Revised (RBS-R)[37] categorizes as follows.

* Stereotypy is apparently purposeless movement, such as hand flapping, head rolling, or body rocking.
* Comp

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Question?: Pdd Autism

Mary asks…

Does anyone know the cause of autism? How to prevent my soon to be born daughter from having autism?

I’m currently pregnant and wonder if there’s anything I have to do to prevent autism? Is it true that certain vaccines can cause autism? Thank you

admin answers:

There is no known single cause for autism, but it is generally accepted by the medical community that it is caused by abnormalities in brain structure or function. Brain scans show differences in the shape and structure of the brain in autistic versus non-autistic children. Researchers are investigating a number of theories, including the link between heredity, genetics and medical problems. While no one gene has been identified as causing autism, in many families there appears to be a pattern of autism or related disabilities, further supporting a genetic basis to the disorder. Researchers are searching for irregular segments of genetic code that autistic children may have inherited. It also appears that some children are born with a higher susceptibility to autism, but researchers have not yet identified a single “trigger” that causes autism to develop.

Researchers are also investigating the possibility that, under certain conditions, a cluster of unstable genes may interfere with brain development, resulting in autism. Still other researchers are investigating problems during pregnancy or delivery, as well as environmental factors such as viral infections, metabolic imbalances, and exposure to environmental chemicals.

Autism tends to occur more frequently than expected among individuals who have certain medical conditions, including Fragile X syndrome, tuberous sclerosis, congenital rubella syndrome, and untreated phenylketonuria (PKU). Some harmful substances ingested during pregnancy have also been associated with an increased risk of autism. Early in 2002, The Agency for Toxic Substances and Disease Registry (ATSDR) prepared a review of hazardous chemical exposures and autism and found no compelling evidence for an association. However, there was very limited research and more needs to be done to rule out chemicals.

The question regarding a relationship between vaccines and autism continues to be debated. In 2001, an investigation by a committee of the Institute of Medicine concluded that the “evidence favors rejection of a causal relationship…. Between MMR vaccines and autistic spectrum disorders (ASD).” The committee however, acknowledged that “they could not rule out” the possibility that the MMR vaccine could contribute to ASD in a small number of children. While other researchers agree the data does not support a link between the MMR and autism, they also agree more research is clearly needed.

Whatever the cause, it is clear that children with autism and PDD are born with the disorder or born with the potential to develop it. Bad parenting does not cause it. It is not a mental illness. Children with autism are not unruly kids who choose not to behave. Furthermore, no known psychological factors in the development of a child have been shown to cause autism.

Http://www.autism-society.org/site/PageServer?pagename=WhatIsAutism

If you are a normal healthy individual do not worry about any thing and keep yourself cheerful and healthy. Do the physical exersises as adviced by your Doctors regularly and think positively. Wish you all the best.

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Question?: Autism Symptoms In 6 Year Old

Mandy asks…

What are your tips about tutoring an 8 year old with Autism?

He is in the 2nd grade and he can read on the 2nd grade reading level though his reading comprehension is poor. That is what I’ll be working with him on mostly. I will also be working on his handwriting as his small motor skills are not strong. His speech delay puts his communication level at about 4 years old.

I will be working with him 3 times a week.

admin answers:

First be sure you know what it is…

Autism is a brain development disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old.[2] The autism spectrum disorders (ASD) also include related conditions with milder signs and symptoms.[3]

Autism has a strong genetic basis, although the genetics of autism are complex and it is unclear whether ASD is explained more by multigene interactions or by rare mutations.[4] In rare cases, autism is strongly associated with agents that cause birth defects.[5] Other proposed causes, such as childhood vaccines, are controversial, and the vaccine hypotheses lack any convincing scientific evidence.[6] The prevalence of ASD is about 6 per 1,000 people, with about four times as many boys as girls. The number of people known to have autism has increased dramatically since the 1980s, partly due to changes in diagnostic practice; the question of whether actual prevalence has increased is unresolved.[7]

Autism affects many parts of the brain; how this occurs is not understood. Parents usually notice signs in the first two years of their child’s life. Although early behavioral or cognitive intervention can help children gain self-care, social, and communication skills, there is no known cure.[3] Few children with autism live independently after reaching adulthood, but some become successful,[8] and an autistic culture has developed, with some seeking a cure and others believing that autism is a condition rather than a disorder.[9]

Second…

Autistic kids often have one particular thing that they are focused on and love. I.E. Cars, or trains, or scooby doo. Figure out what that is and incorporate it into your tutoring. This will help keep their attention.

Third…

Do your research.. There is HUNDEREDS of sights on the internet about working with Autistic children.

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Question?: Schizophrenia Stories

Paul asks…

delusions schizophrenia stories?

why does it seem that people of color may suffer from the diease schizophrenia than non or the poorer class i have found that out to be true.

admin answers:

People used to think it was because minorities and working class people were subject to more stress and thus more likely to suffer from severe mental disorders. Recent research suggests that schizophrenic disorders and major mood disorders have more of a biological or genetic basis and the stress theories have kind of went out the window. A better explanation is that Caucasian people are more likely to be diagnosed with bipolar disorder and minorities are more likely to be diagnosed with schizophrenia. The two disorders, in acute phases, can be very difficult to distinguish. Schizophrenia, mania and severe depression can all involve delusions, hallucinations, catatonia, agitation, anxiety and sleeplessness.

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Aspergers in Toddlers

Asperger Syndrome (AS), also called Asperger’s, is a disorder in the autism spectrum disorder (ASD) range. It is characterized by repetitive and restrictive patterns of interests and behaviors, and difficulties in social interaction. It is not as severe as some of the other ASDs because cognitive and linguistic development does not tend to be impacted. There are several generalized symptoms of the disorder, particularly clumsiness, atypical use of language, limited empathy, and limited or no nonverbal communication skills. The disorder is named after the Austrian pediatrician, Hans Asperger, who first noticed these symptoms in children in his practice in 1944. Today, with the knowledge modern medicine has regarding neurology and symptoms, Aspergers in toddlers may be diagnosed much sooner than in previous decades.

No one knows the exact cause of Asperger’s, although there is a suspected genetic basis. Most people diagnosed with the disorder improve as they mature, and although there is no one treatment or cure, people with the syndrome can manage the worst of their symptoms with behavioral therapy. Some people with AS deal with social and communication problems their whole lives.

The symptoms of Aspergers in toddlers are usually present, although the diagnosis is usually not made until the child reaches seven or nine years of age. Early warning signs may allow a diagnosis to be made much sooner, which would benefit a child who may receive therapy to help with the worst of the symptoms. Some kids with Asperger’s fail to attain milestones like crawling, waving, other simple gestures, and unassisted standing within the first year. These kids may also fail to make eye contact, show an aversion to affection, and may prefer being alone. Repetitive behaviors may also appear in the first year or two, like rocking.

Other symptoms of Aspergers in toddlers include abnormal non-verbal communication, lack of social skills, advanced language development, poor coordination – clumsiness, reflex abnormalities, delayed concept of joint attention, delayed use of gestures, delayed pointing, preoccupation with certain topics or items, early reading, sensitivity to stimuli, and obsession with complex topics.

Children with an autism spectrum disorder like Aspergers may begin to develop verbal communication or social skills, but then start to lose those skills around age three. The sooner an autistic or Asperger’s Syndrome child is diagnosed, the sooner behavioral therapy can begin. Early treatment can sometimes lessen the severity of the disorder and help the child to be more able to get along in life. Speak to your doctor if you feel your child may have Aspergers disorder.

Register for your FREE webinar training now and discover the key to unlocking childhood Autism and Aspergers syndrome.
autismininfants.org

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Identifying Autism Risk In High Risk Siblings Of Children With ASD

Main Category: Autism
Article Date: 19 May 2012 – 0:00 PDT Current ratings for:
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By focusing on the identification of common genetic variants, researchers have identified 57 single nucleotide polymorphisms (SNPs) that predict – with a high degree of certainty – the risk that siblings of children with Autism Spectrum Disorder (ASD) will also develop the condition. The findings were presented at the International Meeting for Autism Research.

ASD is among the most common form of severe developmental disability with prevalence rates up to 1 in 88 children. Boys are greater than four times more likely to be diagnosed with ASD, while recurrence risks for the sibling of a child with ASD are estimated at 18.7%. Since multiple studies have shown that early assessment and intervention offer significantly improved long-term outcomes, early identification of children at risk of ASD has become a key goal.

Though many recent studies demonstrate that autism has a genetic basis, the inheritance pattern of ASD in most families is highly complex. While genetic testing for autism has been limited to the identification of copy number variants (CNVs), autism-associated CNVs are found only in approximately 10% of children with ASD.

Researchers seeking an alternative approach to identify biomarkers for autism have focused on a number of common genetic variants – or SNPs – that have been shown to be related to the risk of ASD. While individual SNPs do not cause ASD, recent studies have shown that the presence of a combination of autism-associated SNPs can predict with a high degree of certainty whether a child will develop ASD.

“By looking at a combination of gender-specific, risk-associated, genetic common variants, we were able to identify siblings of children with ASD who have a significantly increased risk of developing autism,” says lead author Francois Liebaert, MD, Vice President of Research and Development for IntegraGen, SA, Evry, France, “Earlier identification of siblings of children with autism at increased risk may lead to faster referrals, earlier diagnosis, earlier intervention and better prognosis. We also hope to replicate these findings in families that do not have a child with autism.”

These findings build upon earlier identification of eight autism-related SNPs that occur in males and females (Autism risk assessment in siblings of affected children using sex-specific genetic scores) published in Molecular Autism.

To determine which SNPs were associated with autism, researchers applied techniques that have been used to analyze other complex diseases. By combining statistical results from genome wide association studies (GWAS) with biological information from multiple sources including databases and scientific literature, the researchers were able to identify and prioritize the SNPs, and develop gender-specific genetic scores to predict the risk of autism.

The study comprised greater than 1,100 families which have more than one child diagnosed with ASD, referred to as multiplex families, including nearly 2,000 affected and 600 unaffected siblings. The male to female ratio for affected children was close to 4.2:1. The discovery cohort included 545 families from the Autism Speaks Autism Genetic Resource Exchange Repository (AGRE). The findings were then replicated in a population comprising 627 families including 339 families from a separate AGRE collection and DNA samples from 288 independent families collected at the University of Washington, Seattle and currently maintained at the University of Pennsylvania.

External collaborators included Gerald Schellenberg, Ph.D. and Beth Dombroski, Ph.D. from the Department of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine, Philadelphia, PA and Geraldine Dawson, Ph.D., Professor of Psychiatry at the University of North Carolina, Chapel Hill and Chief Scientific Officer, Autism Speaks.

SNPs associated with an increased risk of autism were identified by performing four separate GWAS on the AGRE discovery cohort: the first using all affected children; then two separate GWAS using affected males and affected females; and a final GWAS limited to unaffected siblings. Each SNP identified in the GWAS studies received a score based on the summation of their individual statistical and available biological information. SNPs that scored higher than the defined threshold underwent further analysis to measure the strength of their association with autism using validated statistical methods to measure the estimated reproducibility of results in a larger population. The authors then constructed gender-specific genetic scoring models using the sum of individual risk associated SNPS. The ability of these gender-specific genetic scores to discriminate siblings with or without ASD was then evaluated.

“Combining statistical and functional genomic data, as was done with this study, increases the ability to separate signal from noise when conducting GWAS to identify common variants associated with complex illnesses like autism,” stated Emmanuelle Génin, Ph.D., Research Director, Population Genetics, National French Institute for Health and Medical Research (INSERM, CEPH), Paris, France. “Since autism is a heterogeneous syndrome with a complex genetic etiology, this approach increases the likelihood of reproducibility of the findings across independent population cohorts.”

This research found 57 SNPS that maintained their association with autism in both the initial research and the replication studies in addition to the eight SNPs identified in the previously published study. The 57 SNPs included 26 SNPs which were associated with autism in males only, 26 in females only, and 5 SNPs which were associated with autism in both males and females. Males and females identified as having a significantly increased risk of developing autism were reported to have a two and four fold increased risk of autism, respectively, compared to the average sibling of a child with autism.

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Genetic Systems Disrupted In Autistic Brain

Main Category: Autism
Also Included In: Genetics
Article Date: 03 May 2012 – 1:00 PDT

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Autism has a strong genetic basis, but so far efforts to identify the responsible genes have had mixed results. The reason for this is that autism is influenced by many different genes, and different genes are involved in different individuals, making it hard to find the common genetic ground between patients.

Now, research conducted at the Hebrew University of Jerusalem has shown that despite this fact, the different genes involved in autism tend to be involved in specific processes in the brain. This can explain, on the one hand, similarities in the behavioral symptoms of different autistics, but also the large spectrum of behaviors observed in different autistic individuals.

The Hebrew University research, conducted by Dr. Sagiv Shifman and his doctoral student Eyal Ben-David of the Department of Genetics at the Alexander Silberman Institute of Life Sciences, has potential implications for early diagnosis as well as for treatment of autism in the future. The study was recently published in the journal PLoS Genetics.

Autism spectrum disorders are neurodevelopmental syndromes characterized by social deficits, language impairments and repetitive behaviors. Recent studies indicate that autism is considerably more common than previously supposed, with a prevalence rate that is high as 1% in some regions.

The main goal of the Hebrew University project was to test the contribution of rare genetic mutations, as well as the genetic variations which are common in the population, and to see whether these different types of genetic risk factors are related. Instead of testing individual genes, the researchers chose to study gene collections, in an attempt to understand general pathways involved in autism.

To that end the scientists constructed a network based on the expression pattern of genes across different brain areas. This allowed them to discover groups of genes with shared function in the brain. Next, based on genetic data from thousands of families with autistic children, the researchers studied the contribution of different groups of genes to autism.

To their surprise, they found — when looking at mutations found in autism as well as thousands of common gene variants that are more frequently seen in autistics — that these mutations and variations are located in specific functional groups.

When looking at families with one autistic individual (sporadic cases), and in families where there is more than one affected individual (multiplex cases), the same variants were seen acting in both cases. These groups of genes are highly active in the first year of life, and are involved in processes of learning, memory, and sensory perception.

The Hebrew University scientists believe that their work could pave the way for large-scale genetic scans in the future that could allow for early diagnosis of autism. Further, the results of their study provide a ray of hope that by concentrating on specific gene groups, it will one day be possible to design drugs which could alleviate symptoms.

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Scattered Across Many Genes, Autism Mutations Merge Into Common Network Of Interactions

Main Category: Autism
Also Included In: Genetics
Article Date: 09 Apr 2012 – 0:00 PDT

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University of Washington researchers announced their findings from a major study looking into the genetic basis of autism spectrum disorders (ASD) with an approach piloted at the UW. Their results are reported in the advanced online edition of the journal Nature.

The researchers have been studying ASD in children who have no family history of this or related impairments – so called “sporadic autism” – and also why autism varies in its symptoms and severity. By focusing on “sporadic autism,” the researchers sought to evaluate a specific genetic model for ASD risk, namely the appearance of new mutations (termed de novo) in children with ASD that were not found in either parent.

By uncovering new gene mutations that disrupt the function of proteins, the researchers have discovered a pathway related to modifying chromatin – the tightly coiled spools of DNA in the cell – and to regulating genes in the brain and nervous system. Various changes in this pathway contribute to children developing autism in different ways. Mutations in this pathway also may contribute to a variety of childhood intellectual, social, and psychiatric disabilities, with implications beyond autism.

To identify these new mutations, the researchers used the latest sequencing technologies and analytical methods to determine the sequence of the protein-coding portion of the human genome, called the “exome,” in family trios (father, mother, and child). This approach was piloted this past year at the University of Washington with an initial set of 20 autism families. The pilot demonstrated the technical feasibility and potential impact of this approach.

For the current study, the researchers expanded the project to include 677 individuals from 209 families with a single child with autism. They also sequenced the exomes of 50 unaffected brothers and sisters. In the newly reported results, 248 de novo mutations were validated, and 120 of these were classified as severe. These were predicted to produce, for example, proteins that were truncated or malfunctioning. The researchers then narrowed in on 60 top candidates most likely to contribute to autism risk, based on the nature of the mutation, functional evidence, or previous studies.

“It is important to point out that in each generation there is on average one new coding mutation per child and not all of these will cause developmental problems. However, in the case of children with autism, what we are finding are disruptions in many genes that are known to directly interact and also look similar to genes previous associated with autism,” said Dr. Brian J. O’Roak, a senior fellow in the Department of Genome Sciences working with senior authors Drs. Jay Shendure and Evan Eichler. In fact, researchers found that 49 of the genes mutated had products known to directly interact by forming a highly interconnected network.

Interestingly, many of the proteins in this pathway are important in terms of remodeling chromatin – changing the way DNA is packaged in the cell – and controlling the expression and function of other genes and proteins. These protein pathways are thought to be critical in brain cell formation, brain cell connections, and nerve-cell signaling.

Having this large data set also allowed the researchers to evaluate the parental source of these new mutations, that is, whether they came from the sperm of the father or egg of the mother. Their analysis revealed that the new mutations were overwhelming paternal in origin (in a ratio of 4:1). Their results confirmed a prediction population geneticist J.B.S. Haldane made in in 1935. Moreover, the new mutations occurred at a rate that correlated with the age of the father. These findings, they said, support other studies that show older fathers have a slightly increased risk of having a child with an autism spectrum disorder.

What is also very clear from this study and two additional studies appearing concurrently in the same issue of Nature is that autism risk mutations are scattered across many genes. One of the other studies was led by Mount Sinai Medical Center in New York, the second by Yale University in New Haven.

In the UW study, recurrent protein-altering mutations were discovered in only two genes, NTNG1, and CHD8. The data suggest that, at the molecular level, there are many different forms of autism and that the term “autism spectrum disorder” is better thought of as an umbrella disorder with many root causes. The authors predict that although no single gene will account for more than 1 percent of autism, collectively all of these rare mutations will account for much of the genetic basis of the disease.

While this level of complexity is a major challenge for the field, the authors are already working on a solution using next-generation sequencing approaches. To tackle this challenge, the researchers implemented a new cost-effective screening technology that allowed them to screen more than 2,500 inviduals for mutations in six genes in only a month. In so doing they found strong evidence for the involvement of a glutamate receptor gene GRIN2B for a subset of cases with autism. This same approach will allow the authors to screen all of the newly discovered genes to rapidly test which ones are truly disease-causing.

Among the other genes they discovered with de novo mutations in children with autism, several have been previously implicated in intellectual disability and developmental delay. This indicates, the authors said, that the divisions clinicians made between these various types of diseases in children may not readily translate into differences at the molecular level. The researchers added that it is still uncertain whether there are subsets of people with autism who share a common or strongly related causative mechanism in their underlying molecular biology, or how large those groups might be.

Article adapted by Medical News Today from original press release. Click ‘references’ tab above for source.
Visit our autism section for the latest news on this subject. In addition to O’Roak, Shendure, and Eichler, other researchers on the study were Laura Vives, Santhosh Girirajan, Emre Karakoc, Nik Krumm, Bradly P.Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith, Emily H. Turner, Ian B. Stanaway, Benjamin Vernot, Maika Malig, Carl Baker, Beau Reilly, Joshua M. Akey, Elhanan Borenstein, Mark J. Rieder, and Deborah A. Nickerson, all from the UW Department of Genome Sciences, and Rapheal Bernier, of the UW Department of Psychiatry and Behavioral Sciences. Eichler is also a investigator with the Howard Hughes Medical Institute, and Borenstein also holds appointments in the UW Department of Computer Science and Engineering and at the Santa Fe Institute.
This project was supported by the Simons Foundation Autism Research Initiative, the National Institutes of Health, and the Howard Hughes Research Institute. The authors have declared competing financial interests, which are published with their Nature manuscript.
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‘Scattered Across Many Genes, Autism Mutations Merge Into Common Network Of Interactions’

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