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

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; Renzo Guerrini; William B. Dobyns

doi:10.1172/JCI.INSIGHT.87623

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

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 BurkeSondhya 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, Renzo Guerrini, William B. Dobyns

Pediatric Genetics & Metabolism

Research output: Contribution to journal › Article › peer-review

106 Scopus citations

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 targetedpanel 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.

Original language	English (US)
Article number	e87623
Journal	JCI Insight
Volume	1
Issue number	9
DOIs	https://doi.org/10.1172/JCI.INSIGHT.87623
State	Published - Jun 16 2016

Bibliographical note

Funding Information:
We thank the patients, their families, and referring providers for their support of our research, and the Macrocephaly-Capillary Malformation (M-CM) Network (https://www.m-cm.net/) for their support as well. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health under award numbers K08NS092898 (to G. Mirzaa), R01NS092772 and R01HL130996 (to W. Dobyns), by the EU Seventh Framework Programme (FP7) under the project DESIRE grant agreement N602531, E-Rare JTC 2011 (to R. Guerrini), and the Wellcome Trust under grant number 102731 (to A. Goriely). G. Mirzaa and W.B. Dobyns had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources have no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.

Publisher Copyright:
© The Author(s), 2016.

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10.1172/JCI.INSIGHT.87623

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Mirzaa, G., Timms, A. E., Conti, V., Boyle, E. A., Girisha, K. M., Martin, B., Kircher, M., Olds, C., Juusola, J., Collins, S., Park, K., Carter, M., Glass, I., Krägeloh-Mann, I., Chitayat, D., Parikh, A. S., Bradshaw, R., Torti, E., Braddock, S., ... Dobyns, W. B. (2016). PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight, 1(9), [e87623]. https://doi.org/10.1172/JCI.INSIGHT.87623

Mirzaa, G, Timms, AE, Conti, V, Boyle, EA, Girisha, KM, Martin, B, Kircher, M, Olds, C, Juusola, J, Collins, S, Park, K, Carter, M, Glass, I, Krägeloh-Mann, I, Chitayat, D, Parikh, AS, Bradshaw, R, Torti, E, Braddock, S, Burke, L, Ghedia, S, Stephan, M, Stewart, F, Prasad, C, Napier, M, Saitta, S, Straussberg, R, Gabbett, M, O’Connor, BC, Keegan, CE, Yin, LJ, Meeng Lai, AH, Martin, N, McKinnon, M, Addor, MC, Boccuto, L, Schwartz, CE, Lanoel, A, Conway, RL, Devriendt, K, Tatton-Brown, K, Pierpont, ME, Painter, M, Worgan, L, Reggin, J, Hennekam, R, Tsuchiya, K, Pritchard, CC, Aracena, M, Gripp, KW, Cordisco, M, van Esch, H, Garavelli, L, Curry, C, Goriely, A, Kayserilli, H, Shendure, J, Graham, J, Guerrini, R & Dobyns, WB 2016, 'PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution', JCI Insight, vol. 1, no. 9, e87623. https://doi.org/10.1172/JCI.INSIGHT.87623

@article{d505946e478648bf81db5aa649c3833c,

title = "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 targetedpanel 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.",

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

note = "Funding Information: We thank the patients, their families, and referring providers for their support of our research, and the Macrocephaly-Capillary Malformation (M-CM) Network (https://www.m-cm.net/) for their support as well. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health under award numbers K08NS092898 (to G. Mirzaa), R01NS092772 and R01HL130996 (to W. Dobyns), by the EU Seventh Framework Programme (FP7) under the project DESIRE grant agreement N602531, E-Rare JTC 2011 (to R. Guerrini), and the Wellcome Trust under grant number 102731 (to A. Goriely). G. Mirzaa and W.B. Dobyns had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources have no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} The Author(s), 2016.",

year = "2016",

month = jun,

day = "16",

doi = "10.1172/JCI.INSIGHT.87623",

language = "English (US)",

volume = "1",

journal = "JCI insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "9",

}

TY - JOUR

T1 - PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

AU - Mirzaa, Ghayda

AU - Timms, Andrew E.

AU - Conti, Valerio

AU - Boyle, Evan August

AU - Girisha, Katta M.

AU - Martin, Beth

AU - Kircher, Martin

AU - Olds, Carissa

AU - Juusola, Jane

AU - Collins, Sarah

AU - Park, Kaylee

AU - Carter, Melissa

AU - Glass, Ian

AU - Krägeloh-Mann, Inge

AU - Chitayat, David

AU - Parikh, Aditi Shah

AU - Bradshaw, Rachael

AU - Torti, Erin

AU - Braddock, Stephen

AU - Burke, Leah

AU - Ghedia, Sondhya

AU - Stephan, Mark

AU - Stewart, Fiona

AU - Prasad, Chitra

AU - Napier, Melanie

AU - Saitta, Sulagna

AU - Straussberg, Rachel

AU - Gabbett, Michael

AU - O’Connor, Bridget C.

AU - Keegan, Catherine E.

AU - Yin, Lim Jiin

AU - Meeng Lai, Angeline Hwei

AU - Martin, Nicole

AU - McKinnon, Margaret

AU - Addor, Marie Claude

AU - Boccuto, Luigi

AU - Schwartz, Charles E.

AU - Lanoel, Agustina

AU - Conway, Robert L.

AU - Devriendt, Koenraad

AU - Tatton-Brown, Katrina

AU - Pierpont, Mary Ella

AU - Painter, Michael

AU - Worgan, Lisa

AU - Reggin, James

AU - Hennekam, Raoul

AU - Tsuchiya, Karen

AU - Pritchard, Colin C.

AU - Aracena, Mariana

AU - Gripp, Karen W.

AU - Cordisco, Maria

AU - van Esch, Hilde

AU - Garavelli, Livia

AU - Curry, Cynthia

AU - Goriely, Anne

AU - Kayserilli, Hulya

AU - Shendure, Jay

AU - Graham, John

AU - Guerrini, Renzo

AU - Dobyns, William B.

N1 - Funding Information: We thank the patients, their families, and referring providers for their support of our research, and the Macrocephaly-Capillary Malformation (M-CM) Network (https://www.m-cm.net/) for their support as well. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health under award numbers K08NS092898 (to G. Mirzaa), R01NS092772 and R01HL130996 (to W. Dobyns), by the EU Seventh Framework Programme (FP7) under the project DESIRE grant agreement N602531, E-Rare JTC 2011 (to R. Guerrini), and the Wellcome Trust under grant number 102731 (to A. Goriely). G. Mirzaa and W.B. Dobyns had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources have no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. Publisher Copyright: © The Author(s), 2016.

PY - 2016/6/16

Y1 - 2016/6/16

N2 - 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 targetedpanel 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.

AB - 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 targetedpanel 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.

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

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