Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome

Am J Hum Genet. 2012 Jun 8;90(6):1108-15. doi: 10.1016/j.ajhg.2012.05.006. Epub 2012 May 31.

Abstract

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) is a sporadically occurring, nonhereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. We hypothesized that CLOVES syndrome would be caused by a somatic mutation arising during early embryonic development. Therefore, we employed massively parallel sequencing to search for somatic mosaic mutations in fresh, frozen, or fixed archival tissue from six affected individuals. We identified mutations in PIK3CA in all six individuals, and mutant allele frequencies ranged from 3% to 30% in affected tissue from multiple embryonic lineages. Interestingly, these same mutations have been identified in cancer cells, in which they increase phosphoinositide-3-kinase activity. We conclude that CLOVES is caused by postzygotic activating mutations in PIK3CA. The application of similar sequencing strategies will probably identify additional genetic causes for sporadically occurring, nonheritable malformations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Catalysis
  • Child, Preschool
  • Class I Phosphatidylinositol 3-Kinases
  • DNA Mutational Analysis
  • Female
  • Humans
  • Hypertrophy
  • Infant
  • Lipoma / genetics*
  • Lipoma / metabolism
  • Magnetic Resonance Imaging / methods
  • Male
  • Models, Genetic
  • Mosaicism
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics*

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human