At the moment, about 15-20% of cases of autism have an identifiable genetic component. Most of this is comprised of rare (<1%) mutations that have comparatively high penetrance for autism and other neurodevelopmental conditions, while very little is currently known of common genetic variants that likely also play complex roles in autism susceptibility.
At least in the case of rare mutations, genetic testing such as Chromosomal Microarray Analysis (CMA) and Whole-exome Sequencing (WES) offer a substantial means for identifying disease-related mutations in autism in the future and may become a standard procedure during initial diagnostic assessment as these methods become less expensive and more readily available to physicians. The more this type of precision medicine is used, the more we will undoubtedly learn about the different causes of autism and its heterogeneity.
A recent study published in JAMA this month reports on the relationship in autism between multiple physical anomalies and the identification of rare mutations found through CMA and WES. By classing their subjects into separate groups according to the number of major and minor physical anomalies (essential = 0-3; equivocal = 4-5; complex = 6+), Tammimies et al. found that 37.5% of individuals rated as complex had identifiable mutations as determined via CMA and/or WES, compared to only 6.3% of the essential group. The equivocal group meanwhile hovered in between at a rate of 28.6%. Therefore, the presence of multiple, even minor physical anomalies in a case drastically increases the likelihood that the individual harbors a rare mutation responsible for both the neurological and physical phenotypes.
It should be noted that about 65% of the total number of cases were ranked as essential, indicating that these types of physical anomalies occur in the minority, albeit a large minority. In addition, IQ did not vary significantly across the three groups (which I found particularly surprising) and the age at diagnosis was later in the complex group for unknown reasons.
Though Whole-exome Sequencing was performed on fewer individuals in this study compared to the CMA, the authors feel that the WES will eventually become the sequencing method of choice in the future of autism diagnostics. Hopefully, with the Obama administration’s Precision Medicine Initiative, more funding will go into making WES available for everyday clinical practice.
Not only will we continue to split autism into smaller and smaller subgroups until it’s no longer considered a “disorder” in and of itself but a complex manifestation of some other condition (e.g., Creatine Deficiency), but that knowledge may allow us to intervene medicinally in some cases (application of oral creatine monohydrate to improve cerebral creatine levels) or in others simply to predict progression or other medical complications.
Eventually, as we identify a wider array of common genetic variants that I suspect play weaker though important roles in autism susceptibility– especially amongst the higher-functioning ranges–, WES may be used to identify and understand the etiologies of those conditions as well and we may continue to subgroup individuals according to heredity and teratogenicity.
I suspect that some day “autism” will no longer be considered a diagnostic entity but will be a descriptive akin to “intellectual disability”, and the term “idiopathic autism” will be intended strictly as a temporary and tentative placeholder while further investigation is pursued.
