Child Mental Health for Pediatric Clinicians

07. What causes autism w/ Dr. John Constantino and why genetic testing is so important

• Elise Fallucco • Season 1 • Episode 7

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 What causes autism? Why are there so many more boys than girls with autism? And why is it so important to make sure that children with autism have genetic testing? 
 We discuss this with our guest, Dr. John N. Constantino, child and adolescent psychiatrist and international expert in Autism Spectrum Disorder.

* Boys tend to be more sensitive than girls to genetic risk for autism.

*GENES CAUSE AUTISM
 ** 3/4 of the genetic risk is inherited 
  ---- mainly polygenic risk, which means it requires multiple different gene hits to be involved
----- also  rarely some chromosomal rearrangements
**1/4 of genetic risk is NOT inherited
---- due to  de novo or germline mutations:  DNA changes in the sperm or the egg that makes the baby, that are NOT present in the parents, but are just in the child. 

** It's so important to follow the American College of Medical Genetics recommendations and get genetic testing for our kids with known diagnosis of autism so that we can better understand what caused their form of autism. 

About Dr. John Constantino: His research focuses on understanding genetic and environmental influences on autism spectrum disorder and their implications for treatment and prevention. He developed a well-validated, normed instrument to assess impairments in social-communication skills called the Social Responsiveness Scale (SRS-2). He currently serves as Chief of Behavioral and Mental Health at Children’s Hospital of Atlanta. He has been recognized for his work by numerous awards including the prestigious George Tarjan Award from the American Academy of Child and Adolescent Psychiatry for significant contributions  to the understanding and care of those with developmental disabilities.

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Dr. Elise Fallucco:

Welcome back to PsychEd4Peds helping you help kids. I'm your host, Dr. Elise Fallucco, Child psychiatrist and mom Today, we're continuing our conversation with Dr. John Constantino, international expert on autism. And if you want to hear more about his thoughts about clinical diagnosis of autism, please see our previous podcast. Today, We're going to tackle what do we know about who is at risk for autism? And also, learn why it's so important to make sure that every child in our practice with autism has had thorough genetic testing. So Dr. Constantino, We know that there are significantly more boys than girls who are diagnosed with autism and clinical experience would suggest that maybe it's easier to detect autism in boys than in girls. So can you talk a little bit about this difference in autism by sex?

Dr. Constantino:

It turns out like many things, males tend to wear their symptoms on their sleeves a little more than females do. And so the problematic aspects of behavior become more apparent, in males than in females. But I wanna frame the context of this in an important way. So this issue has been very carefully studied using standardized ratings in epidemiologic populations. If you measure autism symptomatology in a gender normed, standardized way, What you learn is that for an equal level of autism symptom burden, there will be somewhat more of a tendency for boys to be identified than girls. That tendency to be recognized as having autism more if you're a boy than if you're a girl based on the best information that we have so far, would only account for a fraction of the true sex difference in prevalence and diagnosis of the condition. So it can account for some of it, but not the majority of it. The best evidence that we have is the prospective studies of the infant siblings of children affected by autism. And if you track the babies that are born into families where there's an older sibling with autism, And this has been done now for thousands of families. When you do those studies in babies as they're developing to identify who is developing autism and who isn't within families affected by autism, the sex ratio remains 2.5 to one by close observation, using unbiased ratings of these observations. You are seeing these robust ratios in babies. The sex ratio is apparent by the time they are two years old, not little later when, boys and girls are showing different kind of sex norm behaviors. By the time they're two, the sex ratio is in full force at least a 2.5 to one ratio.

Dr. Elise Fallucco:

The sex difference is real for sure. It's real. It's real. Twice as many boys who truly are experiencing autism than there are girls. There's something protective potentially about being a girl in terms of your risk of manifesting or, reaching the threshold of having autism.

Dr. Constantino:

Yeah, we used to think it was a female protective effect, but the evidence has shifted more based on very recent research that we've done in collaboration with many partners. It sounds like a little bit of a mincing of words, but it's probably that males are more sensitive to the genetic influences on autism than females. And so in some ways it's a semantic issue. But when you really get into the weeds of it, if females are really protected from autism, then the sisters of boys with autism would have a very high likelihood of transmitting autism to their sons. And it turns out that they don't. It's a little elevated, but it's much less than you would predict. It really looks like a, an effect of males just being more sensitive to the genetic influences that confer susceptibility. A D H D is another good example of something that kind of works like that in the psychopathologies.

Dr. Elise Fallucco:

Where we would just naturally see more boys who are experiencing the psychopathology than girls.

Dr. Constantino:

Maybe not as much of a sex difference on the inattention symptoms, but probably a sex bias on the more impulsivity and hyperactivity types of symptoms which again, play into what we observe clinically.

Dr. Elise Fallucco:

We know that there is a heritability of autism spectrum disorder. But getting back to the pediatrician's office. So you have a family in there. Let's say dad has a known diagnosis of autism spectrum disorder. Yeah. And then the child screens positive. Does that make you think any differently about the positive screen?

Dr. Constantino:

Sure. The more common scenario is when a sibling or a relative is affected. For parents, it turns out the more severe autism is, the more it lowers the likelihood of reproduction, mating and having children. Really most autism occurs among children whose parents don't have autism. That's what's most common. There's a couple of ironies about genetics of autism that, that are, that are kind of nuances, but they're very important, and it gets confusing to very educated audiences about autism, but, It is a fact that about three quarters of the causal influence on all cases of autism in the community is inherited.

Dr. Elise Fallucco:

Okay. Let's pause right here. Cause you just shared two facts that seem potentially contradictory. Three quarters of autism cases are inherited. Yet most children with autism have parents who don't have autism. So how can children inherit risks for autism if their parents don't have autism? To help understand this, you've told me before that we have to imagine that the genes that confer risk for autism act almost like recessive genes where a parent can carry one allele or one copy and not show signs of the disorder. And it's only when you have enough collective burden from both parents who carry genes. That you get full manifestation of this disorder. Is that sort of how we could think about it?

Dr. Constantino:

Right And among the inherited causes, it's mostly polygenic risk, like all psychiatric disorders. And the polygenic risk tests are not good enough or, have enough prediction to really be useful in autism yet. So let's set that aside.

Dr. Elise Fallucco:

And when you talk about polygenic risk, what you mean is that it's not a single gene that causes autism, but rather a combination or accumulation of multiple gene variants that are associated with increased risk for autism.

Dr. Constantino:

Right Then there are the rare genetic events like chromosomal rearrangements that can be inherited, because they're not so deleterious that they impair reproduction, but they can be players in recurrence of autism within a family or, passing along risk among family members. And this would get back to your example, Elise, of a parent who is carrying, let's say, for example, a chromosomal rearrangement that they themselves are. You know, not too far off of typical, if not completely typical. And so there are known rearrangements like the 22q11.2 deletion 16p11.2 deletion that are really worth identifying. And they can be identified easily by microarray, which is an easy test. And these chromosomal rearrangements are pretty common in the population. And again, mom or dad may have tolerated them, but they may be a very significant player in risk for the child. And they also identify other medical complications or sibling risks, et cetera, that are very important, for the family, to understand.

Dr. Elise Fallucco:

So just to summarize three quarters of cases of autism are inherited. And the vast majority of those are largely poly genic risk, but there's also some risks, rarely have chromosomal rearrangements, and finding out about these inherited causes is really important because then we learn about potential medical complications as well as future risks for the family. So shifting gears, what about the quarter of risk for autism or whatever percentage that is not inherited? Tell us how that comes about.

Dr. Constantino:

The other thing that can happen in autism is it can be caused, by de novo genetic variants. This is especially true for children who are born with autism, whose parents really don't have any sign or symptoms of autism. So neither of the parents have that in their brain or body, but the mutation arose in sperm or egg that formed that baby, and that becomes part of the baby's entire genetic makeup, including their brain. So dad and mom are, going along and they're typically developing individuals and they're walking around some, you know, stray radiation or something hits an ovary or a sperm cell or whatever, Nicks a brain gene, which, produces a chromosomal rearrangement within that sperm or egg cell that gets inherited and that becomes part of that baby's whole body. now you're testing the baby for a de novo variant, a germline variant. And truly about somewhere between 15 and 30% of all autism cases, more among those with intellectual disability, you're gonna get a hit for a known de novo or an inherited mild variant. if you do a set of genetic tests, clinical genomic testing in a person with autism, you're gonna find something. And the American College of Medical Genetics has made the recommendation that all children affected by autism or diagnosed with autism should get chromosomal microarray. And then if chromosomal microarray is negative, get whole exome sequencing. And these are very important because they have implications for reproductive counseling for the family. So if you have a 22 Q 1.2 deletion that the parent is lucky enough to not have any symptoms from, but the child is really experiencing a lot of symptoms a subsequent child has a 50 50 chance of getting that same rearrangement, and that's a very high, risk for a family thinking about, recurrence, and if it's associated with a known syndrome, then. There are potential treatments, there are potential medical complications. If there isn't a known treatment for the syndrome, that the family can know that they are potential participants in the discovery process for that condition. So for all of those reasons, children with autism should be tested genetically. And there's a lot of harangue about will insurance pay for it. Medicaid is actually getting better and better about paying for, at least first line genomic testing of chromosomal micro rate. Not in every state. It varies. But I really do encourage primary care physicians to advocate or to promote following those American College of Medical genetics guidelines and first step chromosomal, microarray and second step whole exome sequencing.

Dr. Elise Fallucco:

Absolutely. You gave the most beautiful description of what's the difference between inherited and de novo mutations and, yeah. That was wonderful. And I like the idea of walking by something radioactive and my DNA getting

um,

Dr. Elise Fallucco:

that will keep me up at night.

Dr. Constantino:

And the older mom and dad gets, the more chances there are for that to happen. And that's why you see parental age effects on the rates for de novo chromosomal rearrangements and sequence variants affecting offspring.

Dr. Elise Fallucco:

What I've seen in my own clinical practice is that I have a lot of older kids with autism who were diagnosed before these American College of Medical Genetics guidelines came out. Yes. And they have never had genetic testing. And I think it'd be super helpful for pediatric clinicians of all types to be reminded, we need to talk to our families about this and not just assume that whoever made the diagnosis also did the genetic testing, because of all the implications for the family and reproductive health, et cetera, and planning.

Dr. Constantino:

Absolutely. Think about it like we can run the table on the entire human genome. So wild. It's incredible. Historically, and you have to be careful how you ask the question of. Was your child genetically tested? Because there's children that are, 30 years old now, and the families will say yeah, they got tested. But what they got tested was a karyotype, not microray, a rearrangement that was so large that it was visible under light microscopy. And so some parents of young adults will say, yes, my, my child was genetically tested. They were tested by light microscopy, by karyotype, and not by these advanced, molecular diagnostic methods that we have now available that have, they've changed everything in genetic diagnosis

Dr. Elise Fallucco:

these are all really important things to keep in mind, dealing with our older kids, teenagers, and even adults that we know with autism How old were they when they were tested and what kind of testing did they have?

Dr. Constantino:

I'll give an example too, of a family that was in my practice a young adult man who had been historically tested by karyotype and found to have nothing. Mother and father and all of his maternal aunts had children with a developmental disorder. And all those children were males. And to make a long story short, when that young man was exome sequenced, he was discovered to have a maternal inherited X-linked sequence variant. Very rare. the sisters and the daughters of these aunts who are now entering reproductive age, this boy's, cousins, they're carrying this x-linked sequence variant that if they have, sons, they're gonna get this syndrome. We were able to give these daughters the test and let them know whether or not they had a 50 50 chance of having a son with a very severe disabling x-linked developmental disorder, that it included intellectual disability, and autism.

Dr. Elise Fallucco:

in that case I'm imagining being the sister of your patient, knowing just vaguely, even before then, oh, there are a lot of children with intellectual disability within our family tree. But what does that really mean? But to have an actual test that'll tell you, yes, you need to worry about this, or No, this, you're not affected by that. That could be really critical information.

Dr. Constantino:

And some families don't wanna know, and that's okay. But some families do wanna know if there's a significant recurrence risk to be able to prepare themselves and their families to responsibly do their own part in, in readying themselves for what might be a higher care requirement for bringing their new baby into the world. I think there's still lots of important things that can be said about just knowing.

Dr. Elise Fallucco:

To tie things back to something we talked about earlier, This idea of the importance of just knowing can be so empowering and helpful. going back to the 24 month old child who has a sibling with autism and the 24 month old screens positive on the MCHAT. In scenario one, that family waits years to be seen by the Center for Autism Related Disorders or whatever the local version is for their evaluation and doesn't really know. In scenario two, the pediatric clinician feels comfortable making the diagnosis. Like we talked about in our previous podcast. And for families just knowing that their child has autism can empower parents just knowing, I think can be really valuable for the family because it, it affects how they parent, it affects how they understand the child. And I've had some kids in my practice where, The parents are relieved when their child is diagnosed with autism because now they understand and they're like, this child isn't purposely avoiding me or ignoring me, or, causing social disruptions When we try to go out in public, it really just has to do with how my child's brain interacts with the environment and there are things I can do to try to help my child.

Dr. Constantino:

And it's not my fault because autism isn't caused by bad parenting. Correct? Correct. Ever. Let me say that again. Autism is not caused by bad parenting or, inexperienced parenting or anything like that. And you're right. Elise and I think your audience, it's very important that they help parents and families be disabused of that, you know, idea.

Dr. Elise Fallucco:

So it can be so helpful to know about the genetic risk of autism, especially when you're talking to families to remind them this has nothing to do with parenting. And really just all has to do with DNA. As an overview and an overall summary of what we've talked about, boys tend to be more sensitive than girls to genetic risk for autism. Three quarters of the genetic risk is inherited and is mainly poly genic risk, which means it requires multiple different gene hits to be involved. Then rarely some chromosomal rearrangements, and then the minority of risk is due to de novo or germline. Variations that have to do. With. DNA changes in the sperm or the egg that makes the baby, and they're not going to be present in the parents, but are just in the child. And bottom line is it's so important. To follow the American college of medical genetics recommendations and get genetic testing for our kids with known diagnosis of autism so that we can better understand what caused their form of autism. And also to be able to share that information if relevant with the rest of the family. so your take home for pediatric clinicians would be,

Dr. Constantino:

I would say feel empowered. To every extent that you can empower yourselves, empower families.

Dr. Elise Fallucco:

Thank you Dr. John Constantino for taking time out of your really busy day to help all of these pediatric clinicians and for sharing your expertise.

Dr. Constantino:

Thank you Dr. Elise Fallucco, for what you're doing and getting the word out and choosing a topic that's so important.

Dr. Elise Fallucco:

Absolutely. I will let you go and continue to take excellent care of children and families. And we'd love to have you back sometime in the future. And for our listeners. Thank you so much for joining us at PsychEd4Peds. Please find us on social media at psyched4peds or online at psyched4peds.Com we'd love to hear from you. So shoot us a message about what you're interested in learning about.