Measurement of head circumference is a common practice in the care of a developing child as it is a high yield, low cost clinical test to monitor brain development. Macrocephaly, or head circumference greater than two standard deviations above the mean (>98th %ile), can be caused by abnormal brain growth, impaired cerebral spinal fluid drainage, or bone growth. While head circumference is a normally distributed trait with normal variations in the population, extreme variants in head circumference are often associated with underlying disease pathogenesis and, in many cases, accompanying behavioral phenotypes. Understanding the causes of reproducible macrocephaly allows us to better grasp the governing principles of brain growth and furthermore the associated behavioral abnormalities. The clinical workup for a child presenting with macrocephaly is important as it not only dictates testing, but also can be indicative of a more insidious disease process with comorbidities. With the wide spread use of massively parallel sequencing technologies the genetic etiologies of numerous de novo, sporadic, and rare genetic syndromes have been recently discovered. We have used this powerful detection tool to identify mutations in a cohort of cases with Macrocephaly. We present the phenotypic information for cases with identified mutations in the genes PTEN, Ptch1, SUFU, mTOR, and DICER1. Furthermore we have modeled these mutations in human cell lines and show that their mechanism of action converges on activation of mTOR signaling. Lastly we demonstrate that infection of with Toxoplasmosis Gondi mirrors this mTOR activation and explains why congenital infections manifest with macrocephaly. We have dissected the exact molecular mechanism resulting from each mutation and proposed novel precision medical approaches to treat these and future cases. The work presented in this dissertation demonstrates the power and utility of a precision medical approach to patients presenting with rare disease and abnormal phenotypes.