As the disease modeling field is developing both more reliable in vitro protocols for neural differentiation and more accurate phenotypical functional readouts, researchers are beginning to explore neurological diseases that have more complex etiologies. While highly penetrant monogenic disorders such as Rett and Fragile X syndromes remain among the most tractable areas for iPSC research, the majority of CNS diseases are multigenic, have incomplete penetrance, and are subject to significant environmental influences. One way to circumvent the variability in phenotypes is to stratify the population of patients. Selecting for specific clinical cohorts such as biologically relevant measures, i.e., the brain size phenotype, drug responsiveness, endophenotypes, or specific genetic cohorts containing specific genetic variations with clinical relevance, can provide valuable information toward patient-tailored biomarkers and therapies.
