PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution
Ghayda Mirzaa, … , Renzo Guerrini, William B. Dobyns
Ghayda Mirzaa, … , Renzo Guerrini, William B. Dobyns
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e87623. https://doi.org/10.1172/jci.insight.87623.
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Research Article Genetics

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

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.

Authors

Ghayda Mirzaa, Andrew E. Timms, Valerio Conti, Evan August Boyle, Katta M. Girisha, Beth Martin, Martin Kircher, Carissa Olds, Jane Juusola, Sarah Collins, Kaylee Park, Melissa Carter, Ian Glass, Inge Krägeloh-Mann, David Chitayat, Aditi Shah Parikh, Rachael Bradshaw, Erin Torti, Stephen Braddock, Leah Burke, Sondhya Ghedia, Mark Stephan, Fiona Stewart, Chitra Prasad, Melanie Napier, Sulagna Saitta, Rachel Straussberg, Michael Gabbett, Bridget C. O’Connor, Catherine E. Keegan, Lim Jiin Yin, Angeline Hwei Meeng Lai, Nicole Martin, Margaret McKinnon, Marie-Claude Addor, Luigi Boccuto, Charles E. Schwartz, Agustina Lanoel, Robert L. Conway, Koenraad Devriendt, Katrina Tatton-Brown, Mary Ella Pierpont, Michael Painter, Lisa Worgan, James Reggin, Raoul Hennekam, Karen Tsuchiya, Colin C. Pritchard, Mariana Aracena, Karen W. Gripp, Maria Cordisco, Hilde Van Esch, Livia Garavelli, Cynthia Curry, Anne Goriely, Hulya Kayserilli, Jay Shendure, John Graham Jr., Renzo Guerrini, William B. Dobyns

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Figure 3

Clinical photographs of MCAP patients.

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Clinical photographs of MCAP patients. (A) Facial photograph of patient ...
(A) Facial photograph of patient LR14-323 (p.Arg83Gln). (B–D) Photograph of the face (B), occipital region (C), and left foot (D) of LR13-359 (p.Pro104Leu) showing MEG, occipital capillary malformation, and syndactyly of the second, third, and fourth toes. (E) Computed tomography (CT) image of LR01-060 (p.Pro104Leu) showing the subcutaneous hemangioma (arrowheads). (F) Photograph of the trunk of LR12-080 (p.Arg115Pro) showing cutaneous capillary malformation with midline delineation. (G) Photograph of LR12-365 (p.Asn345Thr) showing diffuse capillary malformations, MEG with a prominent forehead, and postaxial polydactyly of the left hand. (H) Photograph of LR13-036 (p.Glu365Lys) showing MEG, a disproportionately small body, and short extremities (clinically diagnosed with rhizomelic shortening of the extremities). (I) Photograph of LR11-418 (p.Cys378Tyr) showing diffuse capillary malformations and apparent megalencephaly (MEG). (J and K) Photograph of the face (J) and left foot (K) of LR12-330 (p.Glu545Asp) showing clear MEG, capillary malformation of the philtrum, skin laxity of the forehead, and syndactyly of the second, third, and fourth toes. (L and M) Photographs of the face (L) and body (M) of LR13-038 (p.Gly914Arg) showing MEG, reticulated capillary malformations, pigmented nevus of the right arm, and asymmetry of the legs. (N and O) Photographs of the chest (N) and lower extremity (O) of LR12-383 (p.Gly914Arg) showing clear asymmetry of the trunk involving the right breast and overgrowth of the right leg with prominent venous network. (P and Q) photographs of the left (P) and right (Q) feet of LR11-081 (p.Thr1025Ala) showing bilateral asymmetric macrodactyly, sandal-gap toes, and capillary malformations. (R) Photograph of the feet of LR13-169 (p.Ala1035Thr) showing syndactyly of the second, third, and fourth toes on the right, and second and third toes on the left. (S and T) photographs of the face (S) and lower extremities (T) of LR12-328 (p.Met1043Ile) showing facial and body asymmetry, MEG with a prominent forehead, and capillary malformations on the face and body.