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The identification of convergent phenotypes in different models of psychiatric illness highlights robust phenotypes that are more likely to be implicated in disease pathophysiology. Here, we utilize human iPSCs harboring distinct mutations in  DISC1  that have been found in families with major mental illness. One mutation was engineered to mimic the consequences on DISC1 protein of a balanced translocation linked to mental illness in a Scottish pedigree; the other mutation was identified in an American pedigree with a high incidence of mental illness. Directed differentiation of these iPSCs using  NGN2  expression shows rapid conversion to a homogenous population of mature excitatory neurons. Both  DISC1  mutations result in reduced DISC1 protein expression, and show subtle effects on certain presynaptic proteins. In addition, RNA sequencing and qPCR showed decreased expression of  UNC5D, DPP10, PCDHA6 , and  ZNF506  in neurons with both  DISC1  mutations. Longitudinal analysis of neurite outgrowth revealed decreased neurite outgrowth in neurons with each  DISC1  mutation, which was mimicked by  UNC5D  knockdown and rescued by transient upregulation of endogenous  UNC5D . This study shows a narrow range of convergent phenotypes of two mutations found in families with major mental illness, and implicates dysregulated netrin signaling in DISC1 biology.

Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression