Next, we correlated the patients’ HC and their autism symptom severity with gene expression indices in our organoid model in the 4 families used in this study. Despite the small sample size, we found a consistent positive correlation between HC and autism symptom severity with the upregulated modules as well as a negative correlation with the downregulated modules (Figure 2D). The HC z-scores of probands displayed particularly strong correlations with all module’s eigengene and levels of FOXG1 gene expression at TD31 (Figure 2D). However, the module’s eigengenes displayed no correlation with the HC of the unaffected fathers, despite the fathers presenting the same degree of macrocephaly as the probands (see Figure 2E, F). Together, the observed patterns of correlations suggest that the upregulation in the magenta, blue, brown and tan gene network is a maladaptive trait in the probands and that it may represent a pathophysiological antecedent of symptoms.
