A sex ratio of approximately 4:1 in prevalence is nearly universally observed in familial ASD, despite marked heterogeneity in its (primarily autosomal) genetic causes. The mechanisms by which penetrance is reduced in females across diverse autosomal causes of ASD liability?currently referred to as the ?female protective effect? (FPE)5-9 --- remain unknown. Elucidating the mechanisms of FPE will advance our understanding of a host of heterogeneous causes of ASD and holds the potential for illuminating novel and highly potent interventions for a majority of ASD-affected children. The overarching goals of this research project?which is designed to capitalize upon the infrastructure of the IDDRC@WUSTL)--are to predict and elucidate the mechanisms of sex-specific modulation of susceptibility to ASD. The strategy is to take 3 logical (and related) ?next steps? in understanding FPE?which may operate at the level of cell, brain, and/or behavior, and across disparate autosomal causes?to inform new intervention targets relevant to a diversity of familial autistic syndromes.
Specific Aim 1 is designed to inform translational advances in risk prediction and genetic counselling for female carriers of inherited ASD susceptibility and their offspring. Using an internet-based registry of over 20,000 ASD-affected families (http://ianproject.org) in which over 2500 unaffected sisters of ASD probands?now of child-bearing age?were historically characterized for quantitative autistic traits, we will test predictions of offspring ASD risk as a function of sex (of infant) and quantitative variation in maternal phenotype.
Specific Aim 2 is to determine the extent to which categorical and quantitative variation in expression of the ASD phenotype in ?carrier? adult females relate to previously-published neural (brain MRI) signatures of susceptibility and compensatory function in ASD.
Specific Aim 3 is an exploratory aim to develop a preliminary resource for the elucidation of cellular signatures of FPE. We will establish human iPSC-derived neurons from 4 families transmitting separate autosomal ASD-causing variants (each with 2 ASD-affected males and 1 carrier female, 2 cell lines per individual, for a total of 24 cell lines). We will explore whether within-family cellular contrasts are appreciable between affected males and carrier females by examining axon and dendrite morphology as well as the development and function of synapses in the differentiated neurons. If candidate cellular signatures of FPE emerge, we will use these preliminary data to justify subsequent applications (to submit in years 4-5) to pursue a next phase of investigations critically informed by these studies.
The long-term goals of this application are to understand the mechanism by which inherited susceptibility to autism spectrum disorders results in less severe impairment in females than in males. This is especially important since this phenomenon is observed across the majority of familial autistic syndromes, in which susceptibility is believed to be transmitted by autosomal variants (usually not by variations in sex chromosomes). The relevance of this is that interventions which mimic the mechanisms of reduction in severity observed in females can inform interventions that would be applicable to a large proportion of individuals with autism, who are affected by inherited liability across a diversity of genetic pathways.
| Greene, Deanna J; Koller, Jonathan M; Hampton, Jacqueline M et al. (2018) Behavioral interventions for reducing head motion during MRI scans in children. Neuroimage 171:234-245 |
| Maloney, Susan E; Chandler, Krystal C; Anastasaki, Corina et al. (2018) Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. Autism Res 11:44-58 |
| Meert, Kathleen; Telford, Russell; Holubkov, Richard et al. (2018) Paediatric in-hospital cardiac arrest: Factors associated with survival and neurobehavioural outcome one year later. Resuscitation 124:96-105 |
| Garcia, Kara E; Robinson, Emma C; Alexopoulos, Dimitrios et al. (2018) Dynamic patterns of cortical expansion during folding of the preterm human brain. Proc Natl Acad Sci U S A 115:3156-3161 |
| Marrus, Natasha; Eggebrecht, Adam T; Todorov, Alexandre et al. (2018) Walking, Gross Motor Development, and Brain Functional Connectivity in Infants and Toddlers. Cereb Cortex 28:750-763 |
| Pineda, Roberta; Luong, Anhthi; Ryckman, Justin et al. (2018) Pacifier use in newborns: related to socioeconomic status but not to early feeding performance. Acta Paediatr 107:806-810 |
| Ortinau, Cynthia M; Mangin-Heimos, Kathryn; Moen, Joseph et al. (2018) Prenatal to postnatal trajectory of brain growth in complex congenital heart disease. Neuroimage Clin 20:913-922 |
| Guilliams, Kristin P; Fields, Melanie E; Ragan, Dustin K et al. (2018) Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood 131:1012-1021 |
| Marek, Scott; Dosenbach, Nico U F (2018) The frontoparietal network: function, electrophysiology, and importance of individual precision mapping. Dialogues Clin Neurosci 20:133-140 |
| Noguchi, Kevin K; Johnson, Stephen A; Manzella, Francesca M et al. (2018) Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain. Sci Rep 8:5302 |
Showing the most recent 10 out of 188 publications
