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Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations ofPIK3CAhave 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 identifiedPIK3CAmutations in 60 individuals. Several other individuals (n= 12) were identified separately to have mutations inPIK3CAby clinical targeted-panel testing (n= 6), whole-exome sequencing (n= 5), or Sanger sequencing (n= 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 29PIK3CAmutations were novel. We also identified constitutionalPIK3CAmutations in 10 patients. Our molecular data, combined with review of the literature, show thatPIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

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Journal article


JCI Insight

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