Genetic testing framework for neurodevelopmental disorders and epilepsy plus

March 6, 2018
Lauren Miller, MS, LCGC

Not all genetic tests are the same and it is crucial to choose the right test for your patient. Providers often wonder, “How do I know what that right test is?” The answer to that question is there may not be one specific “right” test, but instead a testing algorithm that can be followed based on a patient’s phenotype. Specifically, for the indications of neurodevelopmental disorders (NDDs) and epilepsy plus, a chromosomal microarray (CMA) reflexed to whole exome sequencing (WES) is an appropriate process to follow to ensure the highest diagnostic yield.

NDDs, including autism spectrum disorder (ASD), developmental delay (DD), and intellectual disability (ID), affect up to 15% of children. The etiology of ASD and DD/ID is complex, involving both genetic and environmental factors. A definitive clinical diagnosis often cannot be made due to an ambiguous patient presentation and the presences of co-morbidities. Similarly, patients with epilepsy plus are difficult to clinically diagnose due to the presence of epilepsy in addition to NDDs, dysmorphic features, or other health problems. Genetic testing in both patient groups can pinpoint the underlying cause of the constellation of symptoms. Having a specific genetic diagnosis can greatly impact medical management and improve patient prognosis.

CMA has the highest diagnostic yield for individuals with ASD, DD, ID, and multiple congenital anomalies (MCA). CMA detects deletions and duplications in the genome, known as copy number variants (CNVs). Numerous professional organizations, such as the American College of Medical Genetics and Genomics and the American Academy of Pediatrics, have issued guidelines on the use of CMA as the first-line genetic test for individuals with ASD, DD, ID and MCA. If CMA does not identify a diagnostic finding, then WES, which looks for sequence variants in the genome, is an appropriate next step. A 2015 study reported the molecular diagnostic yield was higher in patients with a NDD who received both CMA and WES, as opposed to just one or the other. However, performing both these genetic tests at the same time is not a cost-effective testing strategy, and would likely not be covered by insurance. Instead, it is recommended to reflex to WES after a non-diagnostic CMA for patients with NDDs, as WES also has a significant diagnostic yield for patients with NDDs.

A similar genetic testing process of ordering CMA first and then reflexing to WES can be applied to patients with epilepsy plus. However, unlike NDDs, there are no published guidelines on genetic testing for patients with epilepsy. There have been suggested algorithms in the literature as well as a proposed medical coverage policy. The American Academy of Neurology (AAN) has proposed a medical coverage policy for the workflow of patients with neurological disease, which includes epilepsy. AAN suggests starting with a clinical evaluation and based on that evaluation choosing either high-yield single gene testing, multigene testing (panels), or CMA as the initial genetic test. If appropriate, this initial genetic testing is then followed by WES.

When following this proposed workflow, providers will be required to decide what is the right initial genetic test to order; single gene testing, panels, or CMA. This decision can primarily be based on the patient’s phenotypic presentation. If there is a very likely genetic condition or a known familial mutation single gene testing may be appropriate. Epilepsy panel testing would be appropriate for patients whose only indication for testing is epilepsy. For patients with epilepsy plus, a CMA is recommended due to a significant diagnostic yield in this patient population. Like the process for patients with NDDs, WES should be considered as a reflex test if a causative mutation was not identified on the initial genetic test.

In summary, genetic testing is a crucial step to end the diagnostic odyssey of patients with NDDs and epilepsy plus.  Determining the right genetic testing algorithm should always start with a clinical evaluation. If on evaluation, a patient presents with any NDDs or epilepsy plus, a provider should order CMA first, and then reflex to WES. This process will ultimately provide the highest diagnostic yield and most importantly, improve patient prognosis. There are always caveats and exceptions so, as always, providers should use their best clinical judgment when following this process.