Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of <i>PIK3CA</i> have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified <i>PIK3CA</i> mutations in 60 individuals. Several other individuals ( <i>n</i> = 12) were identified separately to have mutations in <i>PIK3CA</i> by clinical targeted-panel testing ( <i>n</i> = 6), whole-exome sequencing ( <i>n</i> = 5), or Sanger sequencing ( <i>n</i> = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 <i>PIK3CA</i> mutations were novel. We also identified constitutional <i>PIK3CA</i> mutations in 10 patients. Our molecular data, combined with review of the literature, show that <i>PIK3CA</i> -related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.