How an expert panel evaluates genes for autism genetic tests | Spectrum | Autism Research News (2022)

How an expert panel evaluates genes for autism genetic tests | Spectrum | Autism Research News (1)

Gene screen: A panel of experts sorts through data on autism-linked genes to determine which ones have strong clinical ties to the condition.

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Autism geneticists seem to agree on one thing: There are hundreds of genes potentially linked to the condition. But few agree on which ones should be added to the gene lists or “panels” for the commercial genetic tests that some clinicians rely on.

To sort through the jumble of information, some of the scientists behind the Clinical Genome Resource (ClinGen) — a U.S. federal program for evaluating clinical genetic evidence — formed a group in 2018 called the Intellectual Disability and Autism Gene Curation Expert Panel (GCEP). This group is tasked with keeping researchers, clinicians and laboratories informed about whether current evidence supports clinical testing for any given gene.

(Video) Genetics and Genetic Testing for Autism: Demystifying the Journey to Find a Cause – April 22, 2021

The GCEP started by scrutinizing a set of 156 genes used in more than one commercial test for autism or intellectual disability. In May, the group reported that 117 — 75 percent — reach its evidence bar for a definitive link to one of the conditions, but 22 lacked sufficient evidence for clinical testing; the remaining 17 had “moderate” evidence — enough to support their inclusion on a test, but still in need of more data.

The group faces an almost Sisyphean task: At its current pace of four gene assessments per month, on average, the group would need more than six years to probe the 318 genes still on its list. And new genes — and new data for old genes — emerge all the time.

Spectrum spoke with panel co-chair Christian Schaaf and coordinator Erin Rooney Riggs about the challenges the team faces and the importance of constantly reevaluating an ever-shifting genetic landscape.

This interview has been edited for length and clarity.

Spectrum: How does the GCEP and its process differ from other groups evaluating autism-linked genes?

Erin Rooney Riggs: One big thing that our panel adds is giving people the concept of levels of evidence. One very commonly used resource is OMIM [Online Mendelian Inheritance in Man], and that just catalogs when a gene-disease relationship has been proposed. But it doesn’t really tell you how much or how little evidence there is to support that relationship.

Over the past few years, we’ve seen a wide gradation in the evidence for the genes we’ve evaluated. Some genes have evidence from many different affected individuals, lots of different papers and very good experimental evidence, and we feel very confident in those genes. And then there are other genes where perhaps only a single family or maybe two or three individuals have been reported. With those, we are questioning ourselves: Are we sure about this? Should those genes really be included on panels?

Christian Schaaf: The first struggle that we experience both as clinicians and as molecular geneticists in the diagnostic lab is, which test should we order? There are hundreds of autism genes that appear on only 1 out of 20 panels. How is one gene list better than the other? It’s really difficult to compare.

Sometimes as a clinician, it’s not easy to understand how a given group arrived at a gene’s respective classification or score. The GCEP has probably the most time-intensive approach out of many different groups that evaluate gene-disease relationships. But its greatest advantage, to me, is that it publishes its standard operating procedure and is very transparent as to how they got to the score. So when you as a clinician order a gene panel or exome sequencing and you get a variant on your report, then you can go back and look up the level of evidence that exists for that gene as it was evaluated by a group of experts. And that is particularly helpful.

(Video) The Genetics of Autism Spectrum Disorder

S: It’s interesting that a gene with so little evidence could even end up on a panel.

ERR: That really speaks to how the genetic testing landscape has evolved over time. The way a lot of labs created the first panels, they were just collecting everything that had ever been suggested to be associated with a given disease.

The consequence is that we’re putting all these so-called “genes of uncertain significance” on there. When we find variants in those genes, what do we do? We don’t know a lot about this gene, we can’t apply a lot of the evaluation criteria, and they get classified as a “variant of unknown significance,” or VUS. But when you get a VUS result back as a patient, or as a clinician, it’s incredibly frustrating. What do you do with that information? Is it going to eventually be your answer? Is it just going to sit at VUS for a long time? It’s really hard to deal with that.

S: The panel decided to expand its scope to include new and disputed genes. Why?

ERR: A lot of the individuals in our group have a deep knowledge of the genes in this field. They’re wondering, “Hey, I just read this new paper,” or, “Hey, I’ve been getting a lot of VUS on this particular gene. What’s the evidence level?” At that point, people started writing in with suggestions of genes to evaluate.

CS: In some ways, ClinGen is crowdsourcing. The entire platform is always to be considered a work in progress. It’s never final. It’s always our best effort of evaluating the gene-disease relationship at a given time. We are very aware that that constantly changes, and that we always need to be open to reevaluation and adjustments.

The task is really daunting. We are tasked with evaluating thousands of genes, and we need a huge workforce in order to do that.

ERR: I don’t think it’ll ever be finished.

S: It’s like how people say you can’t try every restaurant in New York City, because by the time you get through them all, there are new ones that have opened.

(Video) Ask the Expert Panel

ERR: Exactly. But to do this at the level that we do takes time. We could spend an entire hour discussing one gene-disease relationship.

CS: And that’s only the discussion. Before that, there’s a whole process that takes many more hours. Our first step is deciding which genes to evaluate in the context of which condition or phenotype. And it’s not always an easy step. Sometimes, a given gene is listed in a database in connection with multiple disease entities. In those cases, we need to decide: Are these distinct entities? Is it a true example of pleiotropy, where variants in one gene can cause multiple traits across multiple diseases? Or is this all one group of disorders? Are there different disease mechanisms? Are there different modes of inheritance? So it’s a lot of work for each and every gene.

S: Are there any implications of the work for genetics researchers?

ERR: I would hope that they would be paying extra attention to the limited or disputed list. I hope they go find us the additional information that we need to move genes off that list. Sometimes what we need is additional functional information. For example, for missense variants, is this common in the population? Is this really doing anything to the protein?

CS: That’s a really important point. When you think about clinical practice, quite often we identify an additional case where a person has a variant. Say there are three case reports out there for the gene. They don’t see value in publishing yet another case report. But our work shows that there is value in doing exactly that. At those early stages, every case report counts.

It’s also helpful if researchers and clinicians publish certain information that helps us assess the level of evidence. How was the variant found? Was it a candidate gene approach? Was it an exome or genome sequencing approach? How was a diagnosis of autism made?

S: How does the panel’s work affect genetic diagnosis of conditions such as autism?

ERR: ClinGen has a patient registry called Genome Connect, for anyone who has had genetic testing, regardless of why and regardless of the result. Through that process, we get a lot of VUS and gene-of-unknown-significance reports. One of our participants had a VUS in a gene of unknown significance, and the registry reached out to us to say, “Hey, it looks like there is more evidence out there. Can you guys evaluate it?” And we did. We were able to say, “Hey, we do actually believe this gene is disease-causing.” And once that is established, then the lab can go back and correctly apply the variant classification criteria and give the patient a more definitive answer.

That’s a good example of how it comes full circle.

(Video) Matthew State, Recent Progress in Autism Genetics

Cite this article:


Can autism be detected by genetic testing? ›

Genetic testing and autism spectrum disorder

Genetic testing looks for causes of ASD but cannot be used to diagnose ASD. Some people with ASD have syndromic ASD, meaning that they have other specific features in addition to having ASD, such as looking different from other people in the family or having birth defects.

What is a method for evaluating genetic influences in autism? ›

Exome sequencing is a more detailed test that looks at the DNA that codes for genes. With this test, we can find the potential cause of autism about 10 to 30 percent of the time, with a greater chance for genetic findings for people who have intellectual disability.

Does 23 and me look for autism genes? ›

Autism Study Reveals No Genetic Associations - 23andMe Blog.

Is there a gene for autism? ›

But less than 1 percent 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.

Who carries the gene for autism? ›

Researchers have assumed that mothers are more likely to pass on autism-promoting gene variants. That's because the rate of autism in women is much lower than that in men, and it is thought that women can carry the same genetic risk factors without having any signs of autism.

What is the most common genetic cause of autism? ›

Fragile X syndrome is the most common identified cause of inherited intellectual disability and the most common known cause of autism or autism spectrum disorders.

Can blood test detect autism? ›

Diagnosing autism spectrum disorder (ASD) can be difficult because there is no medical test, like a blood test, to diagnose the disorder. Doctors look at the child's developmental history and behavior to make a diagnosis. ASD can sometimes be detected at 18 months of age or younger.

What percentage of autism is genetic? ›

Autism is estimated to be 40–80% 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.

How is genetic testing done? ›

Genetic tests are done using a blood or spit sample and results are usually ready in a few weeks. Because we share DNA with our family members, if you are found to have a genetic change, your family members may have the same change.

Is autism hereditary or genetic? ›

Study Finds 80% Risk From Inherited Genes. A new study looking at autism in 5 countries found that 80 percent of autism risk can be traced to inherited genes rather than environmental factors and random mutations.

Does autism run in families? ›

Inheritance. ASD has a tendency to run in families, but the inheritance pattern is usually unknown. People with gene changes associated with ASD generally inherit an increased risk of developing the condition, rather than the condition itself.

Can autism be detected during pregnancy? ›

A routine prenatal ultrasound in the second trimester can identify early signs of Autism Spectrum Disorder (ASD), a new study by Ben-Gurion University of the Negev and Soroka Medical Center has found.

How do they test for autism during pregnancy? ›

Early information: A new test relies on DNA extracted from fetal cells in the mother's blood. A blood test can accurately detect whether a fetus carries large mutations of the kind linked to autism, according to findings from a pilot study.


1. Uses and Misuses of Clinical Genetic Testing in Psychiatry - Francis McMahon
(National Human Genome Research Institute)
2. Levofolinate treatment for autism: What we have learnt so far - E Quadros, SUNY @Synchrony2020
( The BRAIN Foundation)
3. The potential role of epigenetics in sex differences in autism
(Autism Speaks)
4. Webinar : Richard Boles talks about The benefits of genetic testing and autism
(India Autism Center)
5. Ask the Expert Panel
6. The Benefits of Genetic Testing for Treating Autism
(NeurAbilities Healthcare)

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