Person:

Holm, Ingrid

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62–0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65–0.82), but not for female samples (AUC 0.51, 95% CI 0.36–0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58–0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.

Purpose Much information on parental perspectives on the return of individual research results (IRR) in pediatric genomic research is based on hypothetical rather than actual IRR. Our aim was to understand how the expected utility to parents who received IRR on their child from a genetic research study compared to the actual utility of the IRR received. Methods: We conducted individual telephone interviews with parents who received IRR on their child through participation in the Manton Center for Orphan Disease Research Gene Discovery Core (GDC) at Boston Children’s Hospital (BCH). Results: Five themes emerged around the utility that parents expected and actually received from IRR: predictability, management, family planning, finding answers, and helping science and/or families. Parents expressing negative or mixed emotions after IRR return were those who did not receive the utility they expected from the IRR. Conversely, parents who expressed positive emotions were those who received as much or greater utility than expected. Conclusions: Discrepancies between expected and actual utility of IRR affect the experiences of parents and families enrolled in genetic research studies. An informed consent process that fosters realistic expectations between researchers and participants may help to minimize any negative impact on parents and families.