State of the Art of Genetic Testing for Patients with Autism: A Practical Guide for Clinicians

Abstract The explosion in knowledge, technology, and clinical capabilities regarding genetics and genetic testing has expanded greatly in recent years, and these gains have rapidly been applied to individuals with autism. However, most clinicians are unaware or confused in regards to whom to test, what tests to order, and how testing might alter management and improve outcomes. This review will address these issues. Research shows that autism is highly genetic, and while monogenic cases are common, most patients have multiple genes interacting in disease pathogenesis. However, as genetics dictates disease risk, not outcomes, this does not exclude environmental factors. Clinically-actionable genetics test results can be found across the phenotypically-heterogeneous autistic spectrum; thus recommendations are to test everyone. As autism is also highly genetically-heterogeneous, testing should address a wide range of variant types, including both large (historically detected by microarray) and small (detected by sequencing), at least across all genes (exome). Additional specialized testing important in autism diagnostics includes fragile X, mitochondrial DNA, and pharmacogenetics; the latter often informative for which drug to order, at which dose. Recently, whole genome sequencing has emerged as a favorite since all of the above testing, and more, can be performed at a lower total cost than individual test orders. Trio (child plus parents) sequencing is often indicated, especially in more “severe” cases in order to find new (de novo) variants not present in either parent. Additionally, Angelman syndrome testing should be considered in appropriate cases. Current testing provides a precise diagnosis in about one-half of cases with autism. Beyond diagnosis, genetic testing can oftentimes help elucidate potentially-treatable risk factors that predispose the individual patient to develop disease. In this clinician's experience (RGB), this information leads to improved outcomes in as many as one-half of cases. Clinical improvement can occur in “core” autism areas (attention, behavior, anxiety) and/or in co-morbidities (nausea, fatigue, pain), as demonstrated in brief case reports. Practical guidance is provided regarding assisting clinicians to choose the appropriate test(s) and laboratory, as well as how to get testing paid for. Recent cost reductions now allow for most families to benefit from genetic testing.