CCPR: What’s new in psychiatric genetic risk?
Dr. Besterman: In the past 5–10 years, we’ve identified many genetic risk factors for psychiatric illness. Now we need to interpret all this information to inform care, particularly assessment. That includes trying to describe conditions more specifically, as well as thinking about the risks of psychiatric illness and how to reduce those risks. For kids with neurodevelopmental disorders, there are evidence-based guidelines suggesting genetic testing for rare variants. Previously, chromosomal, microarray, and fragile X testing were the standard of care. In the past few years, whole-exome sequencing has enabled the identification of genetic changes related to increased risk of developmental disorders in up to 40% of individuals.

CCPR: How does the identification of genetic risk help these kids?
Dr. Besterman: You can help the patient based on knowledge of the specific genetic disorder; you can offer reproductive counseling and basic emotional support; in some cases you can enroll in clinical trials; and you can find an online group gathering information about the condition. Communities of families and patients play a leading role in driving therapeutic discovery. Families also identify the biggest needs of the patients, and they support fundraising.

CCPR: What does informed consent look like with genetic testing? Are there risks? Should we always encourage genetic testing for kids with developmental challenges?
Dr. Besterman: Informed consent and informed assent (for adolescents or dependent adults) is necessary prior to genetic testing. Most labs can use buccal swabs mailed from home to do genetic testing. Risks include detecting non-paternity (ie, dad is not dad) and finding genetic changes completely unrelated to the thing you’re testing for (eg, breast cancer risk genes). Usually, the family can decide whether they want unrelated genetic results reported. Also, genetic information can be used by life and disability insurance companies when deciding whether to insure, though they can’t use it to deny health coverage because of the Genetic Information Nondiscrimination Act. Families should consider getting insurance before testing if they don’t have it already. For most children with neurodevelopmental disorders, parents will decide whether to go ahead with testing, but for those who need minimal support, the likelihood of a clinically important finding is lower, and families may wait to let the person decide when they are older.

CCPR: As part of informed consent, how often does testing change the care plan?
Dr. Besterman: Genetic testing rarely changes the care plan, although I’ve had cases where we picked up Rett syndrome and started trofinetide, a case where we found PTEN hamartoma syndrome and are now monitoring for cancer, and a patient diagnosed with fragile X whom we are starting on metformin (Gantois I et al, Annu Rev Med 2019;70:167–181).

CCPR: How do you manage the potential guilt parents might have that they passed the condition on to their child?
Dr. Besterman: Many single-gene differences, such as Huntington’s, always lead to the condition, but in most psychiatric conditions this is not the case. So when genetic changes happen de novo it is bad luck, and when they are passed down from parents it is important to note that the genetics add risk but do not guarantee the person will be affected.

CCPR: Is whole-exome sequencing covered by insurance?
Dr. Besterman: Whole-exome sequencing is covered by most private insurance companies for assessing neurodevelopmental disorders such as autism, intellectual disability (ID), global developmental delay, cerebral palsy, and epilepsy. Government-based insurance unfortunately does not cover it as consistently. Exome sequencing is a first-line diagnostic test and looks only at the gene-coding regions, the exons. Whole-genome sequencing looks not only at the gene coding regions, but more broadly at the regulatory regions. The real questions for clinicians are how to talk with families about getting the test and what to do if there’s a positive result. I encourage folks to reach out to medical geneticists or genetic counselors, clinicians who are genetics experts. A shortage of these specialists means that there are often year-long waitlists. There are also companies that do commercial genetic testing and then offer genetic counseling services free of charge. The best way to make sure that they are reputable is to check if they are officially certified by lab oversight bodies (CLIA certification).

CCPR: Is there a role for exome sequencing in psychotic disorders?
Dr. Besterman: Schizophrenia is in the gray zone between disorders like depression and anxiety, and neurodevelopmental disorders like autism and rare neurodevelopmental syndromes. We’re identifying genetic disorders in about 6% of children with psychotic conditions using microarray, exome sequencing, or genome sequencing. And in young kids with psychosis, rates of genetic disorders are approaching 10% (Alkelai A et al, Schizophr Res 2023;252:138–145; Ahn K et al, Mol Psychiatry 2014;19(5):568–572). The Royal College of Psychiatrists in the UK recommends genetic testing for children and teens with psychotic disorders, but no genetic testing is considered standard of care in the US currently. I suspect that will change at some point.

CCPR: Is genetic testing useful for more common psychiatric disorders in children and teens?
Dr. Besterman: For common childhood disorders like depression, anxiety, and OCD, there is no indication for diagnostic genetic testing. Our current diagnostic genetic testing only detects rare variants with a large effect size, and the genetic changes that underlie these disorders are mostly common genetic changes of small effect size. So diagnostic genetic testing like exome sequencing is not informative or indicated. Parents desperate to find an explanation for their child’s psychiatric condition will sometimes ask about genetic testing, and I inform them that even if we were to identify a genetic change, it wouldn’t tell us anything about their child’s psychiatric condition. There is also the risk of finding unexpected “incidental” genetic changes that confer risk for other health conditions. Where genetics have played a role in these conditions is with pharmacogenetic testing, where it is used to look at genes involved in drug metabolism and to choose the right drug or dosage. There’s been controversy for years around whether this improves outcomes. A recent RCT found that kids who got pharmacogenetic testing received less frequent evidence-based treatment than those who did not get tested, which was counterproductive (Vande Voort JL et al, J Am Acad Child Adolesc Psychiatry 2022;61(1):46–55).

CCPR: Your recent paper talked about a 40% heritability for depression (Besterman AD et al, Am J Psychiatry 2025;182(8):728–741). What do you mean when you say heritability?
Dr. Besterman: The word heritability is used colloquially to refer to the general concept of passing on a trait. But it has a technical genetics definition that refers to the specific genetic contribution to a disease. We’re really referring to how much of an observed phenotype, in this case psychiatric phenotype, can be explained through genetics.

CCPR: Can we talk about the heritability of psychiatric disorders? I have parents who feel guilty about their children’s conditions, and I have couples worried about having children who might suffer from their own conditions.
Dr. Besterman: Many parents feel their children are doomed to inherit their conditions. It doesn’t work that way. Your child will probably be at an increased risk of developing these conditions compared to the average person, but there are so many ways to minimize that risk—things like avoiding certain drugs, getting good sleep and exercise, and eating well. Lifestyle factors have an enormous protective ability against mental illnesses. I like to share the Jar Model, a tool developed by Jehannine Austin and Holly Peay, with families. In this model, we use the idea of a jar that needs to be filled to the top with risk factors for someone to have a disease. (Editor’s note: See figure below.) There are different risk factors, both genetic and environmental, that can fill up a person’s jar. But there are also ways to make the jar larger (eg, building psychological resilience, good fitness, good health, etc). Or you could put a lid on top to prevent more risk factors from being dumped inside (eg, avoiding substances and toxic situations). Just because you have one genetic risk doesn’t mean your whole jar is going to get filled to the top.

CCPR: So, if a child is depressed, his jar is overflowing. Does 34% heritability mean that his jar was already about 34% full?
Dr. Besterman: That’s the general idea. But heritability is also not a static measure. How much genetics contributes to a condition may vary over time and depending on the specific individual and context. We might find an average heritability, but even that can vary depending on how you calculate heritability. It can vary widely from twin studies to genome-wide association studies, where we just look for tiny genetic risk factors that are more common in the affected population compared to a control population. These are average ballpark numbers—our best guesses of how much genetics contributes to a specific disease in a population. They don’t apply perfectly to specific individuals. Don’t fixate on a specific number, but use the concept of genetic risk factors, environmental risk factors, and the interaction between the two to help people protect themselves using resilience factors.

CCPR: In autism we talk about over 90% heritability, which argues against concerns about vaccines.
Dr. Besterman: This is important. Autism is one of the more heritable conditions, compared to depression where there seems to be a much larger environmental component. In autism your brain develops in utero, driven by your specific genetic makeup. That’s well established: Many of the critical genes in autism are turned on primarily at early times in stages of development. This is not to say that certain environmental factors couldn’t contribute to the development of autism, but it’s less of a role than in other psychiatric disorders, and vaccines have been rigorously demonstrated not to be associated with an increased risk of autism (Gabis LV et al, Eur J Paediatr Neurol 2022;36:151–158).

CCPR: Is heritability specific? There’s overlap among genes for autism, bipolar disorder, schizophrenia, and ADHD risk.
Dr. Besterman: Historically, neurogenetics and neuropsychiatric genetics focused on monogenic disorders (eg, fragile X syndrome, Angelman syndrome, etc) with some success. But for common psychiatric disorders (depression, schizophrenia, anxiety disorder, eating disorders, basically everything else), we have found that the genetic architecture is polygenic. A change in one individual gene adds a tiny bit of risk. It’s the effect of thousands of changes across many genes that cumulatively confers risk for psychiatric disorders. Some of these tiny changes may increase the risk for multiple psychiatric disorders. So, depending on the exact collection of tiny changes, you might be more predisposed to one psychiatric disorder than the other.

CCPR: In summary, saying, “What’s in the cats is in the kittens” is not a precise way to address heritability with parents?
Dr. Besterman: Listen to their concerns. If a parent feels they caused their child’s condition, spend the session talking about guilt. If their concern is around heritability, a clear understanding of this concept will be very helpful, including whether to recommend diagnostic genetic testing, depending on the specific condition you are talking about. And you need to know whom to reach out to for help and consultation. Have an approach in mind so you can help and support your patients and families the best way possible.

CCPR: How do you help families manage this guilt?
Dr. Besterman: When you can offer an actual genetic diagnosis, mostly for kids with autism and ID, you can say, “I know something important about your child’s developmental difficulties. The genetic difference that we have identified in your child was a random event that occurred during development that you have no control over, and it was just unlucky.” I have had numerous parents break into tears, saying, “This is so relieving. For so many years, I thought I had a sip of wine during pregnancy and that’s what caused it.” This is where the Jar Model can be helpful, offering parents a general understanding of how genetics, environment, and resilience all interact and contribute to a psychiatric disorder. It gives clarity to families about how these things work—how biology underlies these disorders.

CCPR: Parents often worry that their kids will develop a condition that runs in the family. What can we tell them?
Dr. Besterman: I might say, “Because this disorder runs in your family, your child is at a higher risk than the average person in the population, but for most people who have your child’s level of risk, they will not develop it. So there’s still a very high chance that your child will be fine even though their risk is elevated compared to the average person in the population.” Always taking it back to that reference rate, I think, can be helpful.

CCPR: Thank you for your time, Dr. Besterman.

“When genetic changes happen de novo it is bad luck, and when they are passed down from parents it is important to note that the genetics add risk but do not guarantee the person will be affected.”

Aaron Besterman, MD, DFAACAP