A sex ratio of approximately 4:1 in prevalence is nearly universally observed in familial ASD, despite markedheterogeneity in its (primarily autosomal) genetic causes. The mechanisms by which penetrance is reduced infemales 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 ahost of heterogeneous causes of ASD and holds the potential for illuminating novel and highly potentinterventions for a majority of ASD-affected children. The overarching goals of this research project—which isdesigned to capitalize upon the infrastructure of the IDDRC@WUSTL)--are to predict and elucidate themechanisms 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 acrossdisparate autosomal causes—to inform new intervention targets relevant to a diversity of familial autisticsyndromes. Specific Aim 1 is designed to inform translational advances in risk prediction and geneticcounselling for female carriers of inherited ASD susceptibility and their offspring. Using an internet-basedregistry of over 20,000 ASD-affected families (http://ianproject.org) in which over 2500 unaffected sisters ofASD probands—now of child-bearing age—were historically characterized for quantitative autistic traits, we willtest predictions of offspring ASD risk as a function of sex (of infant) and quantitative variation in maternalphenotype. Specific Aim 2 is to determine the extent to which categorical and quantitative variation inexpression 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 developa preliminary resource for the elucidation of cellular signatures of FPE. We will establish human iPSC-derivedneurons from 4 families transmitting separate autosomal ASD-causing variants (each with 2 ASD-affectedmales and 1 carrier female, 2 cell lines per individual, for a total of 24 cell lines). We will explore whetherwithin-family cellular contrasts are appreciable between affected males and carrier females by examining axonand dendrite morphology as well as the development and function of synapses in the differentiated neurons. Ifcandidate cellular signatures of FPE emerge, we will use these preliminary data to justify subsequentapplications (to submit in years 4-5) to pursue a next phase of investigations critically informed by thesestudies.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
