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Is Autism A Chromosomal Abnormality

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Chromosomal Microarray Had Highest Detection Rate For Autism Spectrum Disorder Abnormalities

Chromosomal mutations and their relation to developmental disorders (Ann Lab Med)

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Chromosomal microarray analysis should be considered as a first-tiergenetic diagnostic test for autism spectrum disorders because of its strongability to detect chromosomal abnormalities in patients with these conditions,findings from a study suggested.

Most children with autism spectrum disorders do not havedysmorphic features or other medical problems associated with a recognizablegenetic syndrome, and genetic testing is crucial to identifying the cause forASD in this population, researchers wrote.

The researchers from Massachusetts and China used clinical genetictesting for 461 patients aged 13 months to 15 years from the Autism Consortiumand 472 patients aged 15 months to 22 years from Childrens HospitalBoston who had clinical diagnoses of ASD between January 2006 and December2008. Genetic abnormalities were identified through G-banded karyotype, fragileX testing and chromosomal microarray .

Karyotype testing found abnormal results in 19 of 852 patients , and fragile X testing revealed abnormalities in four of861 patients , according to the researchers.

Ten of 852 patients had normal results according to CMA but exhibitedabnormal karyotype due to balanced rearrangements or unidentified markerchromosome, the researchers noted.

Shen Y.

Causes And Risk Factors

We do not know all of the causes of ASD. However, we have learned that there are likely many causes for multiple types of ASD. There may be many different factors that make a child more likely to have an ASD, including environmental, biologic and genetic factors.

  • Most scientists agree that genes are one of the risk factors that can make a person more likely to develop ASD.4, 19
  • Children who have a sibling with ASD are at a higher risk of also having ASD. 5-10
  • Individuals with certain genetic or chromosomal conditions, such as fragile X syndrome or tuberous sclerosis, can have a greater chance of having ASD. 11-14, 20
  • When taken during pregnancy, the prescription drugs valproic acid and thalidomide have been linked with a higher risk of ASD.15-16
  • There is some evidence that the critical period for developing ASD occurs before, during, and immediately after birth. 17
  • Children born to older parents are at greater risk for having ASD. 18

ASD continues to be an important public health concern. Like the many families living with ASD, CDC wants to find out what causes the disorder. Understanding the factors that make a person more likely to develop ASD will help us learn more about the causes. We are currently working on one of the largest U.S. studies to date, called Study to Explore Early Development . SEED is looking at many possible risk factors for ASD, including genetic, environmental, pregnancy, and behavioral factors.

Neurologic And Medical Symptoms

The Autism Treatment Network is a network of treatment and research centers dedicated to improving medical care for children and adolescents with autism by establishing standards of clinical care based on research and shared clinical practice. Analysis of data provided by the ATN registry is providing important information on the frequency and character of medical problems in children with autism and is developing autism-specific diagnosis and treatment algorithms with the goal of enhancing overall well being for children with autism.

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Epigenetic Hotspots In Autism: Chromosomes 15q And 7q

Genome-wide scans using affected sib-pairs with autism or ASD reveal suggestive or possible linkage to numerous chromosomes, with loci on 1p, 2q, 3p, 7q, 15q and 17q showing the strongest evidence based on replication in independent patient cohorts . Curiously, several of the linkage peaks overlap or are in close proximity to regions that are subject to genomic imprinting on chromosomes 15q1113, 7q2131.31, 7q32.336.3 and possibly 4q2131, 11p11.213 and 13q12.3, with the loci on chromosomes 15q and 7q demonstrating the most compelling evidence for a combination of genetic and epigenetic factors that confer risk for ASD.

Table;1.

How Do These Genes Contribute To Autism

Autism Genetic Complexity Comes to Light

Changes, or mutations, in the DNA of these genes, can lead to having autism spectrum disorder. Some mutations affect a single DNA base pair or letter. In fact, everyone has thousands of these genetic variants. A variant that is found in 1% or more of the population is considered common and is called a single nucleotide polymorphism .

Common variants typically have subtle effects and may work together to contribute to autism. Rare variants, which are found in less than 1% of people, tend to have stronger effects. Many of the mutations linked to autism so far have been rare. It is significantly more difficult to find common variants for autism risk, although some studies are underway.

Other changes, known as copy number variations , show up as deletions or duplications of long stretches of DNA and often include many genes. But mutations that contribute to autism are probably not all in genes, which make up less than 2% of the genome. Researchers are trying to wade into the remaining 98% of the genome to look for irregularities associated with autism. So far, these regions are poorly understood.

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Duplications Of Chromosome 15q11

Duplications of this region were demonstrated in a smaller study of autistic males. In addition to being on the spectrum, the males also expressed other disorders and physical abnormalities such as seizure disorder, development of a hunched back called kyphosis, and epicanthic folds, a skin fold in the upper eyelids.

Another study was completed with around 140 probands on the spectrum, in which around 1% had the duplication. It is important to note that it is only the maternally inherited duplication that leads to ASD. Deleting the single active copy of the gene results in a total loss of expression of the affected gene producing the disease phenotype. In familial cases, duplication of this region from the maternal chromosome gave an increased risk of ASD while from the paternal it had typically no effect.

Diagnostic Criteria And Tools

The behavioral criteria listed in the 1994 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edition, remain the standard for making an autism diagnosis in the United States. The 2000 update DSM-IV-TR made some changes in the accompanying text but did not change the diagnostic criteria. Currently, three subgroups are recognized. Initially, Rett syndrome, OMIM# 312750, and childhood disintegrative disorder were included as PDDs. Discovery of MECP2 mutations as the cause of Rett syndrome, uncertainty about the nosology of childhood disintegrative disorder, plus a growing understanding of the continuity within the autism diagnoses led to adoption of the term ASDs as the favored umbrella designation for AD, AS, and PDD-NOS. It is expected that the DSM-5, due out in 2012 will further simplify the nosology by combining the three subtypes into ASD, with a variety of modifiers such as the degree of mental impairment, neurologic symptoms and, when available, etiology.

To diagnose autistic disorder, i.e. classical autism, one must precisely enumerate the autism symptoms and their age of occurrence using either the DSM-IV criteria or a number of symptom checklists, structured parent interviews, or observation measures, all of which are based on the DSM-IV Diagnostic Criteria Autistic Disorder. The DSM-IV criteria for AD listed in are probably the easiest to use.

Table 1 DSM-IV diagnostic criteria for autistic disorder

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What Types Of Genetic Tests Are Available

Terms like developmental delay or autism spectrum disorder are broad descriptions of clinical features, but they dont tell us the cause of those clinical features, which can make them challenging to treat. Genetic testing can often help parents and providers identify the genetic abnormality underlying the developmental delay and an autism spectrum disorder.

There are four main types of genetic tests available. The oldest is karyotyping, the inspection of chromosomes under a microscope. This test reliably detects changes to segments larger than 10 million base pairs.A test called chromosomal microarray analysis identifies duplications or deletions of DNA too small to show up on a karyotype. Still, a karyotype is necessary to identify instances in which chromosomes evenly trade a chunk of genetic material.

To detect even smaller duplications or deletions, and single base-pair swaps, clinicians must sequence or scan for mutations across single genes. Some clinicians use commercial autism tests that sequence a predetermined set of genes, but these panels often do not include top autism genes.

An alternative is to sequence all of a persons protein-coding DNA or the exome. Clinicians may sequence the exomes of both parents as well as the child to find mutations present in only the child. These spontaneous mutations are more likely to contribute to autism than are inherited ones. Exome sequencing is expensive, however, and often not covered by insurance.

Chromosome Abnormalities Raise Risk For Autism

Genetic Testing for Autism Spectrum disorders

WEDNESDAY, Jan. 9 — Abnormalities on chromosome 16 appear to raise children’s risk for developing autism, a new study suggests.

The discovery, made by a consortium of autism researchers, pinpoints one of the causes of a disorder that is turning out to be as complex in its origins as it is in its symptoms. Not only is autism complicated, its incidence has grown rapidly in recent years, with an estimated one in every 150 children in the United States now struck by the neurological disorder.

“This has given us another piece of the puzzle of the genetics of autism,” said study leader Mark Daly, a member of the Autism Consortium with the Center for Human Genetic Research at Massachusetts General Hospital Center in Boston. “Autism is very complex, and we have only a few pieces in hand. We’re trying to gain an understanding of the biological mechanisms underlying it. This is an opportunity to understand that.”

According to the study, published Jan. 9 in the online edition of the New England Journal of Medicine, a section of chromosome 16 is deleted or duplicated in about 1 percent of people with autism spectrum disorders . About 15 percent of autism cases have known genetic causes.

However, some experts questioned the far-reaching value of the findings.

One advocate felt the discovery was only a drop in a larger sea of unknowns.

The region in question contains about 25 genes that do not yet have a clear connection to the development of autism.

More information

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Imprinting And Epigenetics Of Chromosome 7q In Asd

One of the first regions identified in linkage studies in ASD encompassed most of the long arm of chromosome 7, and subsequent analyses indicated that this likely reflects linkage two susceptibility loci on chromosome 7q . The more centromeric linkage peak lie at 103.63125.95cM on 7q2131.31. Using parent of origin linkage modeling, Lamb et;al. identified a region of excess paternal sharing with a maximum lod score of 1.46 for identity by descent for paternal alleles at 112cM , near an imprinted gene cluster in a region of conserved synteny with mouse chromosome 6 . In humans, the cluster includes two paternally expressed genes, SGCE and the retro-transposon derived paternally expressed gene 10 , both of which were found to be binding targets for Mecp2 in mouse . Additionally, the paraoxonase 1 gene , which has been examined as a candidate gene in ASD , was expressed preferentially from the paternal chromosome in human:mouse somatic cell hybrids . This gene has been extensively evaluated in cardiovascular disease and no evidence for parent of origin effects on allele transmission has been detected in humans or mice , arguing against imprinting in vivo.

Figure;2.Table;4.

Can Genetics Explain Why Boys Are More Likely Than Girls To Have Autism

Girls with autism seem to have more mutations than do boys with the condition. And boys with autism sometimes inherit their mutations from unaffected mothers. Together, these results suggest that girls may be somehow resistant to mutations that contribute to autism spectrum disorder and need a bigger genetic hit to have the condition.

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Clinical Implications And Future Perspectives

When autism was first described, it was hypothesized to be an environmentally caused disease. Decades of research have since revealed that autism is a highly heterogeneous and extremely complex genetic condition. Even though great progress had been made in identifying hundreds of risk genes, very little is known about the different types of modifiers that may exacerbate or ameliorate disease severity. Such modifiers could include epigenetics, sex-linked modifiers, CNVs, double-hit mutations, or environmental factors .

Figure 1. Genetic modifiers in autism spectrum disorder. Autism is estimated to be 4080% heritable. However, both genetic and non-genetic factors modulate the penetrance of risk genes, resulting in a highly heterogeneous disease phenotype for similar pathogenic variants. Examples of genetic modulators include CNV, epigenetics, and double-hit mutations. Examples of non-genetic modifiers include environmental exposures and sex-linked modifiers.

Fluorescence In Situ Hybridization

Genetic Disorder Chromosome Abnormality Genetics Jacobsen ...

Lymphoblastoid cell lines for each proband and selected family members were acquired from the Rutgers University Cell and DNA Repository and cultured using standard techniques. RPCI-11 BACs that defined the boundaries of the selected CNV were acquired from several sources including the Wellcome Trust Sanger Institute and the Roswell Park Cancer Institute. BAC probes were labeled by nick translation using either Spectrum Green or Spectrum Orange fluorescent dyes . FISH was performed using standard techniques. Slides were analyzed with a Zeiss Axioplan 2 fluorescent microscope with a cooled CCD camera and Applied Imaging CytoVision v3.7 software.

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Genetic Causes And Modifiers Of Autism Spectrum Disorder

  • Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States

Autism Spectrum Disorder is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 1020% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.

Epigenetics And The Environment

Autism susceptibility is currently estimated to be 4080% genetic. Environmental factors likely acting through epigenetic regulation as the major mechanism presumably compromise the remainder of the risk. Hundreds of potential environmental factors have been suggested to contribute to risk, such as increased parental age , maternal complications or infections during pregnancy, or prenatal exposure to anticonvulsants . In-depth reviews of these findings can be found elsewhere . In this review, we will only discuss the epigenetic modifying effects of valproic acid an anticonvulsant as one example of the widespread modifications that an environmental factor can induce. Valproic acid has been hypothesized to modify gene expression through histone deacetylase inhibition activity and is sometimes used to induce an autistic phenotype in animal models . Examples of its far-reaching effects include apoptotic cell death in the neocortex, decreased proliferation in the ganglionic eminence, increased homeobox A1 expression, abnormal serotonergic differentiation via Achaete-Scute family BHLH transcription factor 1 silencing, disrupted serotonin homeostasis in the amygdala, dendritic spine loss, reduced prefrontal dopaminergic activity, and disruption of the glutamatergic/GABAergic balance .

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Autism Chromosome: A Look At Genome Studies On Autism

By;Andréas RB Deolinda, BA, BSc

The study of genes has led to the discovery that some genes contribute to deficits in communication, social cognition, and behavior. Individuals diagnosed with autism experience a variety of related symptoms, as such, a growing number of studies have been conducted from physiological studies to genetic studies. These seek to determine the cause of autism in an effort to improve the lifestyle of children with autism by targeting the biological cause of their symptoms.

The core features of autism spectrum disorder include persistent deficits in social communication and social interaction and restricted, repetitive patterns of behavior or interests. Other symptoms include intellectual disability, some experience developmental delay, delayed brain development, pervasive developmental symptoms etc. Due to all these anomalies, autism is generally considered a developmental disorder.

The core features of autism spectrum disorder include persistent deficits in social communication and social interaction and restricted, repetitive patterns of behavior or interests.

According to Rylaarsdam, et al. , other conditions that occur with autism include motor abnormalities, epilepsy, intellectual disability, sleep disorders, and gastrointestinal problems.;

The Treatment Of Speech And Communication Disorders

In autism, genes drive eye gaze abnormalities

ntroductionHave you ever been seen by a therapist due to an injury or simply for recovery? Therapy is defined as treatment projected to heal a certain disorder. Within this field, there are various types of therapy. For example, speech, physical, and occupational therapy. Speech therapy includes the treatment of speech and communication disorders. While physical therapy focuses on the use of exercises and equipment to help patients regain or improve their physical abilities, occupational therapy

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Chromosome 15q: Evidence For A Role In Autism In Cytogenetically Normal Patients

Perhaps surprisingly, genome-wide screens have not consistently identified evidence for linkage to chromosome 15 in ASD cohorts, although application of targeted high-density screening strategies or phenotypic subgroupings has defined a region of interest that extends from the PWS/AS critical region through the cluster of genes encoding -aminobutyric acid receptor subunits . The numerous imprinted and biallelically expressed genes that lie in this region are thus positional candidates, with the genes encoding GABA receptor subunits of particular interest in ASD because of their function in the nervous system.

Both of the maternally expressed genes that lie toward the centromeric end of the candidate region have been specifically investigated in ASD. Using high-density, targeted screening strategies, linkage disequilibrium was detected at both the UBE3A and ATP10A loci in families with autism ; however, mutation screening in two small cohorts of autistic patients did not identify clearly pathological mutations in these genes . Subsequent studies in postmortem brain samples from patients with autism revealed abnormalities in methylation of the UBE3A CpG island as well as decreased UBE3A/E6-AP expression in autism, AS and Rett samples , suggesting that UBE3A misexpression may be a common mechanism for these phenotypically related disorders.

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