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Chromosomal Microarray (CMA) in Children with Psychiatric Disorders: Who to Test and What to Expect

August 9, 2018
Brooke Spangler, MS, LCGC

Chromosomal microarray (CMA), which detects clinically significant copy-number variants (CNVs), has been recognized as a first-tier test for any individual with developmental delay (DD), autism spectrum disorder (ASD), or multiple birth defects (MCA; PMID: 20466091). Testing people with one or more of these indications has led to the discovery of new chromosome deletion and duplication syndromes, and has also uncovered CNVs that increase the risk of psychiatric disorders. For this reason, genetic testing is becoming a reality in psychiatry and CMA can be an important tool for patient care. This shift calls for more genetic education of providers and patients.

While CNVs have not been found to be disease-specific for psychiatric illnesses, many have been confirmed as risk factors for a variety of mental disorders. For example, rare pathogenic deletions (seen in less than 1% of the general population) involving neurexin genes, such as NRXN1, have been associated with neurodevelopmental disorders. The neurexin gene family plays an important role in the formation of synaptic contacts and neurotransmitter signaling, and NRXN1 is specific to glutamatergic synapses (PMID: 18419324). The NRXN1 gene is highly sensitive to dosage changes, where a deletion of one copy of this gene has been found to cause a spectrum of features that include intellectual disability (ID) and various psychiatric disorders, such as ASD, schizophrenia, attention deficit-hyperactivity disorder, and bipolar disorder (PMID: 25614873, 30031152). However, these symptoms can greatly differ from one individual to another (even those within the same family).

The majority of people with symptoms who were identified on CMA with a NRXN1 gene deletion inherited the deletion from a parent; interestingly, many parents have mild or no obvious symptoms. A recent study estimated the chance of symptoms in a person with a NRXN1 deletion to be 46% and suggested that other genetic or environmental influences play a role in the penetrance and expression of the NRXN1-associated symptoms (PMID: 30031152).

Numerous CNVs are known to cause an increased risk for psychiatric disorders, and many produce a wide range of symptoms that may or may not include DD, ASD, or MCA. And knowing future risks can help educate parents and patients, hopefully preventing a sudden crisis (for example, children with 22q11.2 deletion syndrome can be screened for psychiatric issues before age ten years to provide an opportunity for early intervention). CMA is valuable at any age, but many adults with ID or psychiatric disorders do not have a genetic diagnosis. This is likely due to lack of formal evaluation or the fact that testing technology at the time of a clinical diagnosis did not find an answer. One study recently looked at 100 adults with ID and a psychiatric illness or behavioral concern and found that 25 people had a CNV that explained their features. Interestingly, people who had two psychiatric disorders were over four times more likely to have a confirmed or likely disease-causing CNV (PMID: 29882083).

Although many pathogenic CNVs do not correspond to a specific psychiatric condition (and in fact, may be linked to several psychiatric disorders), the information can still be extremely helpful. The International Society of Psychiatric Genetics updated their Genetic Testing Statement in 2017 and recommended CMA testing for people with ASD, schizophrenia, or other psychiatric disorders, especially when accompanied by intellectual disability or other health concerns. Most behaviors and mental health problems are easier to understand and manage once a genetic diagnosis is identified, as it allows for planning of more tailored medical intervention strategies. The ISPG also stated that identifying CNVs may have important medical and psychiatric implications for individuals as well as family members, especially those whose symptoms don’t fit the standard clinical picture (https://ispg.net/genetic-testing-statement/).

How does this information help me care for my patients?
Medical management recommendations or considerations for psychiatric concerns associated with NRXN1 gene deletions, 22q11.2 deletion syndrome, and 15q11.2 BP1-BP2 deletion syndrome include:
  • ADOS assessment for autism spectrum disorder evaluation, followed by Applied Behavior Analysis (ABA) therapy for those who meet diagnosis criteria
  • Potential medication for treatment of ADHD or anxiety
  • Routine screening for symptoms of schizophrenia, bipolar, and other mental health disorders for early detection and initiation of treatment
  • Assess for other chronic medical conditions (e.g., obesity, diabetes, heart disease, and alcohol and substance abuse)
If you would like to speak with a Lineagen genetic counselor to discuss if one of your patients is appropriate for testing, please contact our clinical team by phone at 801-931-6191 or by email at gc-team@lineagen.com.

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