Quo Vadis clinical genomics of ASD?

Almost 40 years ago, Folstein and Rutter (1977) published their seminal twin study on the heritability of autism spectrum disorder (ASD), sparking intense research into the molecular genetic basis of the disorder. Thereafter, the knowledge of genetic causes in ASD and the ability to detect causal mutations have increased substantially due to advances in genomic technologies, such as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS). Recent genetic evidence suggests that in many cases ASD may be a common clinical manifestation of several rare genetic disorders (Geschwind and State, 2015). Therefore, genomic testing has the potential to become an integral part of ASD assessment aiding early diagnosis. Currently, a clinical genetic evaluation is recommend by The American College of Medical Genetics and Genomics (ACMG) for all children with a confirmed clinical ASD diagnosis (Schaefer and Mendelsohn, 2013). Yet, it is unclear how many individuals with ASD are actually referred to a clinical geneticist and the timing of the genetic testing following ASD diagnosis. Thus, it is difficult to judge to what extent the recommendation by the ACMG is followed, and whether genetic testing has an impact on treatment plans and/or outcomes in ASD. Currently, the recommended first tier genetic evaluation is CMA, which detects copy-number variants (CNVs) in the genome. Additional targeted molecular genetic testing is offered if family history, clinical examination or co-existing medical conditions suggest a specific etiology (e.g., fragile X, Rett or Cowden syndrome). But what is the likelihood of providing a molecular diagnosis (molecular diagnostic yield) made possible by genetic testing? Using CMA, approximately 10% of autistic individuals will receive a molecular diagnosis such as deletion or duplication of 16p11.2 or the Dup15q syndrome (Shen et al., 2010; Tammimies et al., 2015). The use of NGS-based wholeexome sequencing (WES) to detect sequence level variants has led to identification of numerous new ASD-genes (e.g. CHD8) (Bernier et al., 2014; De Rubeis et al., 2014; Iossifov et al., 2014), but is still mostly used in research settings. Based on an unselected ASD population, one recent study showed WES to have a molecular diagnostic yield comparable to CMA (Tammimies et al., 2015), but studies on selected research cohorts suggest that the yield could be even higher (Iossifov et al., 2014). Use of wholegenome sequencing (WGS) could potentially increase the molecular diagnostic yield up to 50% as both sequence and copy number level mutations can be detected throughout the genome in a single test (Jiang et al., 2013; Yuen et al., 2015). On the other hand, it is important to emphasize that even if genomic testing could provide a molecular diagnosis to many individuals with ASD, the predictive power to estimate an individual’s functional impairment and outcome based on the testing is probably low. This is mainly because many of the identified genomic and sequence variants confer susceptibility to a range of neuropsychiatric phenotypes that vary in severity (Geschwind and State, 2015) and are also found in individuals that are unaffected or exhibit milder subclinical phenotypes (Mannik et al., 2015; Stefansson et al., 2014). This variable expressivity and incomplete penetrance are most likely due to the effects of genetic background, environmental factors and their interactions which currently cannot be estimated. Therefore, careful genetic counseling explaining the benefits, potential negative impact(s) and uncertainties should be always provided for the family before and after genetic testing. So what are the potential benefits of providing an etiological genetic diagnosis to individuals with ASD and their families? First, most patients and families inquire professionals about the underlying cause of a diagnosed condition, and knowing the cause is often experienced as a relief (Narcisa et al., 2013; Reiff et al., 2015). Causal explanations can promote psychological well-being of the family by relieving guilt and promoting acceptance (Trottier et al., 2013). On the other hand, negative consequences, such as blame in face of the knowledge that one has passed on a genetic condition to the child might also arise (Reiff et al., 2015). Possibly, a positive and constructive family reaction to the identification of a known genetic factor improves long-term outcome, as it might facilitate better understand of the child and therefore enables adequate decisions for the child, such as appropriate educational, occupational and social support networks (Farley et al., 2009; Howlin et al., 2005). Eventually, families could even be enrolled to targeted clinical trials or participate in research investigating novel treatment options for their child based on the detected variant. Second, genetic counseling based on the individual’s genetic results make possible the conveyance of more specific likelihoods of recurrence risk of ASD in the family Quo Vadis clinical genomics of ASD? 635798 AUT0010.1177/1362361316635798AutismEditorial research-article2016