Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.
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.
Department of Pathology, Boston Children's Hospital, MA 02115, USA.
Kyle C
KC
Kurek
Valerie L
VL
Luks
Ugur M
UM
Ayturk
Ahmad I
AI
Alomari
Steven J
SJ
Fishman
Samantha A
SA
Spencer
John B
JB
Mulliken
Margot E
ME
Bowen
Guilherme L
GL
Yamamoto
Harry P W
HP
Kozakewich
Matthew L
ML
Warman
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D002384:Catalysis; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D006984:Hypertrophy; D007223:Infant; D008067:Lipoma / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008957:Models, Genetic; D009030:Mosaicism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human