Title: PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
Authors: Mirzaa, Ghayda ×
Timms, Andrew E
Conti, Valerio
Boyle, Evan August
Girisha, Katta M
Martin, Beth
Kircher, Martin
Olds, Carissa
Juusola, Jane
Collins, Sarah
Park, Kaylee
Carter, Melissa
Glass, Ian
Krägeloh-Mann, Inge
Chitayat, David
Parikh, Aditi Shah
Bradshaw, Rachael
Torti, Erin
Braddock, Stephen
Burke, Leah
Ghedia, Sondhya
Stephan, Mark
Stewart, Fiona
Prasad, Chitra
Napier, Melanie
Saitta, Sulagna
Straussberg, Rachel
Gabbett, Michael
O'Connor, Bridget C
Keegan, Catherine E
Yin, Lim Jiin
Lai, Angeline Hwei Meeng
Martin, Nicole
McKinnon, Margaret
Addor, Marie-Claude
Boccuto, Luigi
Schwartz, Charles E
Lanoel, Agustina
Conway, Robert L
Devriendt, Koenraad
Tatton-Brown, Katrina
Pierpont, Mary Ella
Painter, Michael
Worgan, Lisa
Reggin, James
Hennekam, Raoul
Tsuchiya, Karen
Pritchard, Colin C
Aracena, Mariana
Gripp, Karen W
Cordisco, Maria
Van Esch, Hilde
Garavelli, Livia
Curry, Cynthia
Goriely, Anne
Kayserilli, Hulya
Shendure, Jay
Graham, John
Guerrini, Renzo
Dobyns, William B #
Issue Date: Jun-2016
Publisher: American Society for Clinical Investigation
Series Title: JCI Insight vol:1 issue:9
Article number: e87623
Abstract: Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA 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 PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by 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 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
ISSN: 2379-3708
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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