Autism Genetics: Testing, Karyotyping and Chromosomal Microarray

Autism spectrum disorder is primarily a genetic condition. Most of the risk for autism comes from genes. Mutations in more than 100 genes are known to lead to the condition. Chromosomal abnormalities have been observed in about 3-5 % of autism cases. G-banded karyotype analysis has been a standard method for detecting autism-associated chromosomal abnormalities for about 35 years.

There are four types of tests that can detect these mutations, as well as structural variations that may lead to autism. As researchers learn more about the genetics of autism, the tests have become more informative: More of the mutations they find have ties to autism and to known health consequences.

Microarray analysis should replace G-banded karyotype analysis as the standard genetic test for individuals with an autism spectrum disorder. This recommendation is based on the fact that microarrays have a resolution more than 10 times that of karyotypes as well as a diagnostic yield about 6 times greater. Furthermore, the cost of microarray testing is lower than that of karyotype analysis followed by specific FISH testing.



As the cost of genetic testing decreases and clinical microarrays become more widely available, this technology will almost certainly become a standard aspect of autism diagnosis. As the researchers continue to identify the genetic causes of the numerous subtypes of autism, more and more people on the spectrum can benefit from genetic testing, earlier diagnosis, and earlier intervention.

Appreciation of the multidisciplinary nature of autism will enhance the rate of discovery of autism-associated loci and facilitate improved diagnosis and treatment of individuals with autism, thus improving the lives of individuals and families affected by autism. While progress in autism genetics has made significant contributions to the clinic, much research remains to be done.

Genetic Test for Autism Spectrum Disorder


There is no genetic testing for autism. A genetic test cannot diagnose or detect autism. That’s because myriad genes along with environmental factors may underlie the condition. Roughly 100 genes have clear ties to autism, but no single gene leads to autism every time it is mutated.

Why Would a Person With Autism Get a Genetic Test?


If a test reveals a harmful mutation with known ties to autism spectrum disorder, the result could give the person with autism and their family an explanation for the condition. Some families also find emotional and practical support from others dealing with the same mutation.

There are no drugs tailored to particular autism mutations. But the mutations are often linked to other health problems, such as epilepsy, kidney problems or obesity, so having the information could help prevent or treat those problems.



How Can Testing Help a Child With Autism?


Without genetic testing, it may be difficult for parents to know the true cause of the child’s autism and developmental delay and get the most comprehensive medical management. A genetic diagnosis will also help parents understand:

  • Recurrence risk – the chance that another family member could have the condition
  • Co-morbidity – Seemingly unrelated conditions, like heart disease or seizures, often found to co-occur with your child’s delay
  • Prognosis – How the condition is expected to progress

The more precise genetic tests can be helpful to a small number of parents, sparing the family time and worry en route to a speedier diagnosis. But for the other 90% of kids with autism, their parents can only wait for answers.

What Types of Genetic Tests Are Available?


Terms like developmental delay or autism spectrum disorder are broad descriptions of clinical features, but they don’t 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 person’s 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.

Sequencing the entire genome is the most thorough method. It reveals mutations in any part of a person’s genome, not just the 1% that includes genes. It is still only a research tool, but as its price falls and it becomes more widely available, it could replace the other tests.

For now, American medical academies recommend only karyotyping or chromosomal microarray analysis for autism spectrum disorder. They also advise looking for point mutations in FMR1, MECP2 or PTEN, but only when a child shows other signs of the syndromes associated with mutations in these genes.



G-Banded Karyotype, Fragile X Testing and Chromosomal Microarray Analysis (CMA)


In today’s world, children suspected of having autism are tested for genetic abnormalities with two tests which are the G-banded karyotype, which looks for abnormalities in the chromosomes, and fragile X testing, which looks for a specific variation on the X chromosome. Those two tests find genetic abnormalities in up to 5% of children with autism.

Researchers offered about 933 people aged between 13 months to 22 years who had been diagnosed with an autism spectrum disorder three genetic tests: G-banded karyotype testing, fragile X testing or chromosomal microarray analysis (CMA), which has been available only for the past few years.

Genetic testing in children with autism, specifically high-resolution chromosome studies (karyotype) and DNA analysis for Fragile X, should be performed in the presence of intellectual disability (or if intellectual disability cannot be excluded), if there is a family history of Fragile X or undiagnosed intellectual disability, or if dysmorphic features are present. However, there is little likelihood of positive karyotype or Fragile X testing in the presence of high-functioning autism.

Karyotype tests identified chromosomal aberrations associated with autism in about 2% of patients, while the fragile X genetic mutation was found in about 0.5% of patients.

Standard practice is to offer children with autism two tests as a first-line genetic work-up: karyotype and fragile X testing, the researchers said.
In karyotyping, forms of which have been around since the 1960s, geneticists use a microscope to look for chromosomal abnormalities that are associated with autism. Like karyotyping, Chromosomal microarray (CMA) also looks for chromosomal abnormalities but does so at 100 times the resolution of the earlier test. Chromosomal microarray (CMA), a genome-wide test, can identify sub-microscopic deletions or duplications of DNA sequences, called copy-number variants, known to be associated with autism.



Chromosomal microarray (CMA) testing increases the diagnostic yield over karyotyping in children with the aforementioned characteristics, and CMA testing may impact clinical management decisions. Next-generation sequencing panel testing allows for the simultaneous analysis of a large number of genes and, in patients with normal CMA testing, the next-generation testing has been proposed as a way to identify single-gene causes of syndromes that have autism as a significant clinical feature.

Chromosomal microarray testing may be considered medically necessary as first-line evaluation when a genetic evaluation is desired as opposed to first obtaining a karyotype. Karyotyping is recommended only when there is a suspicion of aneuploidy.

In the new study, researchers used a newer test, chromosomal microarray analysis, to identify variations in much smaller chunks of DNA. That test turned up genetic abnormalities in about 7% of people with autism spectrum disorders, compared with about 2% of people tested with the karyotype method. The researchers point to that 5% point difference and argue that the newer genetic test should be used widely in diagnosing children with autism.

However, even with the better genetic test, about 90% of children diagnosed with autism will have no known genetic cause of their condition. We simply don’t yet have tests capable of finding the subtle genetic cues that play a role in autism, even though children with more severe forms of autism or mental retardation are more likely to have identifiable genetic abnormalities.



What Proportion of People With Autism Spectrum Disorder Find Answers From Genetic Tests?


Relatively few people find answers from genetic testing. Karyotyping finds a relevant mutation in 3% of people with autism, and microarray analysis in 10%. Sequencing the three genes associated with syndromes could identify an autism mutation in 14% of people with autism. Combining these methods with sequencing the exome could yield results in as much as 40% of people with autism.

In one 2015 study, microarrays found mutations that could explain autism in 9%of children with the condition. Sequencing exomes revealed mutations in another 8%. The likelihood of finding a known genetic variant increases if the person with autism also has an intellectual disability, seizures or unusual facial features.

Is There Such a Thing as an Autism Gene?


Of course, therein nor really such as thing called autism gene. There are several conditions associated with autism spectrum disorder that stem from mutations in a single gene, including fragile X and Rett syndromes. But less than 1% of non-syndromic cases of autism stem from mutations in any single gene.

So far, at least, there is no such thing as an ‘autism gene’, meaning that no gene is consistently mutated in every person with autism. There also does not seem to be any gene that causes autism every time it is mutated. Still, the list of genes implicated in autism is growing. Many of these genes are important for communication between neurons or control the expression of other genes.



How Do These Genes Contribute to Autism?


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 (SNP).

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 (CNVs), 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.

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.

Is There a Way to Test for Mutations Before a Child Is Born?


Clinicians routinely screen the chromosomes of a developing baby to identify large chromosomal abnormalities. There are prenatal genetic tests for some syndromes associated with an autism spectrum disorder. But even if a developing baby has these rare mutations, there is no way to know for sure whether he will later be diagnosed with autism.

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