A similar view of diagnostic overlap and specificity is provided by rare, penetrant mutations that are risk factors for multiple psychiatric disorders. Mutations in evolutionarily constrained, fetal-brain expressed genes, many of whose RNAs are bound by the Fragile X mental retardation protein (FMRP) (4, 18, 44, 45), are associated with ASD, SCZ, and intellectual disability (ID), as well as epilepsy. Similarly, few large CNVs are disease-specific, and the most common such mutation, the 22q11-13 deletion, predisposes to both ASD and SZ, as do others (29, 30). The observed variable expressivity is consistent with the hypothesis that large-effect mutations that disrupt highly evolutionarily constrained genes do not lead to a specific clinically defined disorder, but rather increase risk for a range of developmental disorders associated with ID via disruption of the highly canalized process of brain development (46). From this perspective, clinically defined disorders may represent either the limited repertoire or our limited measurements of behavioral responses to the insult. Moreover, the complexity of brain function and structure is not reflected in recognized in current psychiatric disease nosology. This view provides
