Looking Outside of Guidelines for Genetic Testing

April 10, 2018
Guidelines. You use them daily in your practice to make decisions about diagnosing, managing, and treating patients. They are evidence-based, using the relevant studies available at the time they are created. When it comes to ordering genetic testing, guidelines are useful for identifying which patients could benefit from having specific tests.

Current guidelines from several groups, including the AAP, ACMG, and AAN, recommend chromosomal microarray (CMA) as the first genetic test to order for a patient with autism spectrum disorder, developmental delay, intellectual disability, and/or multiple congenital anomalies.[i],[ii],[iii] In part, the evidence used to create these guidelines includes large studies which demonstrated that CMA had a high diagnostic yield for each of those presenting symptoms (studies ranged from 5-25% diagnostic yield).[iv],[v],[vi],[vii],[viii]

However, many of these guidelines were written over five years ago and are based on studies published even longer ago than that. While the guideline clinical indications are a great place to start in determining which patients should have genetic testing, more recent research can also provide guidance for who else may benefit from CMA.
Over the last few years, members of the clinical team here at Lineagen have presented on this topic at scientific meetings. A poster presented as the National Society of Genetic Counselors Conference in 2016 looked at an overall comparison of diagnostic yield between patients with and without indications written in guidelines. This found that patients without “guideline” indications have almost the same diagnostic yield on CMA as patients with “guideline” indications.

The utility of CMA for speech and language delay was evaluated in a poster presented at the International Meeting for Autism Research in 2017. This study found pathogenic variants in 7.2% of children with only speech and language delay. Additionally, patients who only had speech and language delay were tested an average of two years earlier compared to those who did not have that diagnosis, which means that they were able to receive tailored medical management sooner. This demonstrates the value of CMA testing for patients who present with speech and language delays.

At the 2017 American Society of Human Genetics meeting we presented a poster analyzing the detection rate of CMA in individuals with ADD/ADHD. For all patients tested who had ADD/ADHD as a diagnosis, the rate of pathogenic variants was 8.4%. When patients who had a guideline-recommended indication for testing, the diagnostic yield dropped only slightly to 7.2%. This study suggests that CMA may be beneficial in the evaluation of patients with ADD/ADHD.

Cerebral palsy is another diagnosis which has shown high diagnostic yields on CMA. In one study, 9.6% of families had a CMA finding which impacted the diagnosis or classification of cerebral palsy.[ix] Another study found clinically significant variants in 31% of people tested.[x] In a poster at the American Academy of Neurology meeting in 2017, we presented a 9.5% pathogenic rate for patients tested through our laboratory with cerebral palsy as an indication. While study sizes for all of these studies were small, this preliminary data suggests that CMA could be beneficial in identifying the etiology in patients with cerebral palsy.

Several studies have found the diagnostic yield for CMA in patients with epilepsy is similar to that of conditions currently included in guidelines. One study found pathogenic variants in 17.7% of patients while another identified an explanatory variant in at least 5%.[xi],[xii] One center evaluated their cohort of patients with severe early onset epilepsy, finding an overall 17.6% detection rate and 5.9% pathologic variant rate in this population.[xiii] Another study found a 16.7% diagnostic yield on CMA for patients with pediatric drug-resistant epilepsy.[xiv] These studies, as well as others, demonstrate that CMA should be considered in the evaluation of a patient with a seizure disorder.[xv],[xvi]

Even when the underlying presentation is not entirely clear, CMA may be useful. One study looked at the utility of CMA for undiagnosed neurological disorders, which could present with symptoms suggestive of seizures, cerebral palsy, movement disorders, or other similar symptoms. In this group, 9.3% had pathogenic findings, showing that CMA can be useful for patients who have neurological symptoms without a specific diagnosis.[xvii]

Psychiatric conditions are another group of indications for which emerging evidence suggests utility for CMA. Multiples studies have found significant diagnostic yield of CMA for individuals with schizophrenia.[xviii],[xix] The utility has not been as clearly delineated in other psychiatric diagnoses, although studies have identified multiple copy number variants that are associated with conditions such as bipolar disorder and major depressive disorder. As these variants would be detectable by CMA, further research will clarify the value of CMA for patients with these conditions.
Several studies have shown CMA to be valuable in identifying the etiology for congenital heart defects (CHD). The detection rate for isolated CHD has been reported from 4.3-17.9%.[xx],[xxi],[xxii] It has been recommended that CMA be used in the evaluations of patients with isolated CHD.[xxiii]

In addition to what recent studies show, your own expertise and experience may also inform which patients you choose to test. This could be indicated by the clinical complexity of their presentation. It may be a compelling family history that doesn’t seem to fit a specific genetic condition. Your clinical judgment can also be a valuable tool in identifying patients who could benefit from CMA.

In summary, the genetic testing guidelines published by many major medical organizations are a great place to start when determining which of your patients to order CMA for. However, recent medical literature indicates that additional patients may also benefit from CMA testing. Additionally, your clinical expertise and experience can provide insight that can guide you in determining individuals who might not fit guideline criteria but could benefit from CMA. Identifying an underlying genetic etiology, regardless of what the patient’s presenting features may be, will help guide medical management and ensure patients are getting the most appropriate care