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

doi:10.1172/jci.insight.87623

. 2016 Jun 16;1(9):e87623.

doi: 10.1172/jci.insight.87623.

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

Ghayda Mirzaa^{1

2}, Andrew E Timms³, Valerio Conti⁴, Evan August Boyle⁵, Katta M Girisha⁶, Beth Martin⁷, Martin Kircher⁷, Carissa Olds², Jane Juusola⁸, Sarah Collins², Kaylee Park², Melissa Carter⁹, Ian Glass^{1

2}, Inge Krägeloh-Mann¹⁰, David Chitayat^{11

12}, Aditi Shah Parikh¹³, Rachael Bradshaw¹⁴, Erin Torti¹⁴, Stephen Braddock¹⁴, Leah Burke¹⁵, Sondhya Ghedia¹⁶, Mark Stephan¹, Fiona Stewart¹⁷, Chitra Prasad¹⁸, Melanie Napier¹⁸, Sulagna Saitta¹⁹, Rachel Straussberg²⁰, Michael Gabbett²¹, Bridget C O'Connor^{22

23}, Catherine E Keegan^{22

23}, Lim Jiin Yin²⁴, Angeline Hwei Meeng Lai²⁴, Nicole Martin¹², Margaret McKinnon²⁵, Marie-Claude Addor²⁶, Luigi Boccuto²⁷, Charles E Schwartz²⁷, Agustina Lanoel²⁸, Robert L Conway²⁹, Koenraad Devriendt³⁰, Katrina Tatton-Brown³¹, Mary Ella Pierpont³², Michael Painter³³, Lisa Worgan³⁴, James Reggin^{35

36}, Raoul Hennekam³⁷, Karen Tsuchiya^{38

39}, Colin C Pritchard³⁹, Mariana Aracena⁴⁰, Karen W Gripp⁴¹, Maria Cordisco⁴², Hilde Van Esch⁴³, Livia Garavelli⁴⁴, Cynthia Curry⁴⁵, Anne Goriely⁴⁶, Hulya Kayserilli⁴⁷, Jay Shendure^{7

48}, John Graham Jr⁴⁹, Renzo Guerrini⁴, William B Dobyns^{1

2

35}

Affiliations

¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
² Center for Integrative Brain Research and.
³ Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.
⁴ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
⁷ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
⁸ Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.
⁹ Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹⁰ Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
¹¹ Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology, and.
¹² Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.
¹³ Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
¹⁴ Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.
¹⁵ Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.
¹⁶ Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁷ Belfast Health and Social Care Trust, Belfast, United Kingdom.
¹⁸ Genetics, Metabolism and Pediatrics, London, Ontario, Canada.
¹⁹ Clinical Genetics, Center for Personalized Medicine, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.
²⁰ Neurology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
²¹ School of Medicine, Griffith University, Brisbane, Queensland, Australia.
²² Division of Genetics, Department of Pediatrics, and.
²³ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
²⁴ Genetics Service, Department of Pediatric Medicine, KK Women's and Children's Hospital, Singapore.
²⁵ British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia, Canada.
²⁶ Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland.
²⁷ Greenwood Genetic Center, Greenwood, South Carolina, USA.
²⁸ Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina.
²⁹ Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.
³⁰ Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
³¹ South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
³² Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.
³³ Department of Child Neurology, University of Florida, Jacksonville, Florida, USA.
³⁴ Department of Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.
³⁵ Department of Neurology, University of Washington, Seattle, Washington, USA.
³⁶ Providence Child Neurology, Providence Sacred Heart Medical Center and Children's Hospital, Spokane, Washington, USA.
³⁷ Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Laboratories, Seattle Children's Hospital and.
³⁹ Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
⁴⁰ División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.
⁴¹ Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁴² Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
⁴³ Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
⁴⁴ Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.
⁴⁵ University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.
⁴⁶ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
⁴⁷ Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul, Turkey.
⁴⁸ Howard Hughes Medical Institute, Seattle, Washington, USA.
⁴⁹ Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California, USA.

PMID: 27631024
PMCID: PMC5019182
DOI: 10.1172/jci.insight.87623

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

Ghayda Mirzaa et al. JCI Insight. 2016.

. 2016 Jun 16;1(9):e87623.

doi: 10.1172/jci.insight.87623.

Authors

Affiliations

¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
² Center for Integrative Brain Research and.
³ Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington, USA.
⁴ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
⁷ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
⁸ Whole Exome Sequencing Program, GeneDx, Gaithersburg, Maryland, USA.
⁹ Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
¹⁰ Department of Pediatrics, and Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
¹¹ Mount Sinai Hospital, The Prenatal Diagnosis and Medical Genetics Division, Department of Obstetrics and Gynecology, and.
¹² Department of Pediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.
¹³ Center for Human Genetics, University Hospitals Case Medical Center, Cleveland, Ohio, USA.
¹⁴ Department of Pediatrics, Division of Medical Genetics, Saint Louis University, St. Louis, Missouri, USA.
¹⁵ Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA.
¹⁶ Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
¹⁷ Belfast Health and Social Care Trust, Belfast, United Kingdom.
¹⁸ Genetics, Metabolism and Pediatrics, London, Ontario, Canada.
¹⁹ Clinical Genetics, Center for Personalized Medicine, Children's Hospital Los Angeles, Keck School of Medicine at University of Southern California, Los Angeles, California, USA.
²⁰ Neurology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
²¹ School of Medicine, Griffith University, Brisbane, Queensland, Australia.
²² Division of Genetics, Department of Pediatrics, and.
²³ Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
²⁴ Genetics Service, Department of Pediatric Medicine, KK Women's and Children's Hospital, Singapore.
²⁵ British Columbia Medical Genetics Provincial Program, University of British Columbia, Vancouver, British Columbia, Canada.
²⁶ Service de génétique médicale, Centre Hospitalier Universitaire Vaudois CHUV, Switzerland.
²⁷ Greenwood Genetic Center, Greenwood, South Carolina, USA.
²⁸ Department of Dermatology, Children Hospital Prof. Dr. J. P. Garrahan, Buenos Aires, Argentina.
²⁹ Children's Hospital of Michigan, Wayne State University, Detroit, Michigan, USA.
³⁰ Center for Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
³¹ South West Thames Regional Genetics Service, St George's University NHS Foundation Trust, London, and Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
³² Department of Pediatrics and Ophthalmology, University of Minnesota, Minneapolis, Minnesota, USA.
³³ Department of Child Neurology, University of Florida, Jacksonville, Florida, USA.
³⁴ Department of Genetics, Liverpool Hospital, Liverpool, New South Wales, Australia.
³⁵ Department of Neurology, University of Washington, Seattle, Washington, USA.
³⁶ Providence Child Neurology, Providence Sacred Heart Medical Center and Children's Hospital, Spokane, Washington, USA.
³⁷ Department of Pediatrics and Translational Genetics, Department of Pediatrics, Academic Medical Center, University of Amsterdam Medical Center, Amsterdam, The Netherlands.
³⁸ Department of Laboratories, Seattle Children's Hospital and.
³⁹ Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.
⁴⁰ División de Pediatría, Pontificia Universidad Católica de Chile, Pediatra-Genetista, Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago, Chile.
⁴¹ Department of Pediatrics, Sidney Kimmel Medical School at T. Jefferson University, Chief of Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁴² Departments of Dermatology and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
⁴³ Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
⁴⁴ Clinical Genetics Unit, IRCCS Santa Maria Nuova Hospital, Reggio Emilia, Italy.
⁴⁵ University of California, San Francisco, San Francisco/Genetic Medicine Central California, San Francisco, California, USA.
⁴⁶ Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
⁴⁷ Koç University, School of Medicine, Medical Genetics Department, Koç University Hospital, Istanbul, Turkey.
⁴⁸ Howard Hughes Medical Institute, Seattle, Washington, USA.
⁴⁹ Department of Pediatrics, Cedars-Sinai Medical Center, Harbor-UCLA Medical Center, David Geffen School of Medicine Los Angeles, California, USA.

PMID: 27631024
PMCID: PMC5019182
DOI: 10.1172/jci.insight.87623

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.

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Figures

**Figure 1. Levels of mosaicism in *PIK3CA* by sample type.**
Dot blot graph showing alternative allele percentages (AAPs) clustered by type of tissue in all mutation-positive individuals (n = 72). Horizontal bars indicate the mean AAP within each sample type: red = blood (n = 44); blue = saliva (n = 38); orange = skin fibroblasts (n = 26). Two-tailed t test (P values): blood-saliva: P = 0.035; blood-skin: P = 0.036; saliva-skin, P = 0.65.

**Figure 2. Distribution of *PIK3CA* mutations by functional domain in cancer and developmental (pediatric) disorders.**
Graph showing the number of published *PIK3CA* mutations by amino acid location in the Catalogue of Somatic Mutations in Cancer (COSMIC) database of somatic variation in cancer (shown in green; last accessed May 2016) and in children with developmental disorders comparing the megalencephaly-capillary malformation syndrome (MCAP; shown in blue) and all other developmental disorders (shown in orange). Mutations shown include those reported in this study as well as published mutations. Notes: (a) The 2-tailed P value by Fisher’s exact test was less than 0.0001, supporting that the association between MCAP and non-hotspot mutations and non-MCAP and hotspot associations is extremely statistically significant. (b) “Hotspot” mutations in this analysis are the most activating mutations in somatic tissues in cancer (p.Glu542Lys, p.Glu545Lys, p.His1047Arg) (13).

**Figure 3. Clinical photographs of MCAP patients.**
(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.

**Figure 4. Clinical photographs of *PIK3CA* mutation–positive patients with segmental overgrowth.**
(A–D) Photographs at 1 year (A), birth (B), right foot (C), and left foot (D) of LR11-082 (p.Gly106Val) showing diffuse and asymmetric body overgrowth, diffuse capillary malformations, bilateral syndactyly of second, third, and fourth toes, and joint hypermobility. (E–G) Photograph of the body (E and F) and left foot (G) of LR12-070 (Glu453Lys) showing asymmetric overgrowth, capillary malformations with midline delineation, and postsurgical changes after resection of the second toe due to severe macrodactyly. (H and I) Facial photographs of patient LR12-183 (p.Glu542Lys) showing multiple epidermal nevi. (J and K) Photographs of LR12-172 (p.His1047Arg) showing macrodactyly of the left hand.

**Figure 5. Brain MRI images of *PIK3CA* mutation–positive patients.**
(A and B) LR11-082. T1-weighted mid-sagittal (A) and T2-weighted axial (B) image at age 6 months showing a large cerebellum, crowded posterior fossa with cerebellar tonsillar ectopia, and a relatively normal cortical gyral pattern (arrowhead). (C) LR12-184. T1-weighted mid-sagittal image showing marked cerebellar tonsillar ectopia (arrowhead). (D–H) LR12-183. T1-weighted mid-sagittal (D), T2-weighted axial (E and G), and coronal (F) images showing diffuse cortical dysplasia, partial agenesis of the corpus callosum, dysplasia/hypoplasia of the cerebellar vermis and hemispheres, diffuse dysmyelination, abnormal high T2 signal intensities in the red nuclei and thalami bilaterally (red arrows in E and F), and a very large tectum (red arrow in D). (H and I) LR13-197. T1-weighted mid-sagittal (H) and T2-weighted axial (I) images showing bilateral cortical dysplasia, hippocampal dysplasia, white matter dysmyelination, and bilaterally dysplastic ventricles. There is mild cerebellar tonsillar ectopia (arrow in H).

**Figure 6. The PI3K-AKT-MTOR–related developmental brain disorders spectrum.**
Diagram showing the PI3K-AKT-MTOR pathway highlighting genes associated with developmental brain disorders including *PIK3CA*, *PIK3R2*, *PTEN*, *AKT3*, *MTOR*, *CCND2*, *DEPDC5*, *NPRL2*, and *NPRL3* (shown in blue), as well as *TSC1* and *TSC2* genes (shown in red).

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References

1. Vattathil S, Scheet P. Extensive hidden genomic mosaicism revealed in normal tissue. Am J Hum Genet. 2016;98(3):571–578. doi: 10.1016/j.ajhg.2016.02.003. - DOI - PMC - PubMed
1. Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14(5):307–320. - PubMed
1. Zellweger H, Abbo G. Chromosomal mosaicism and mongolism. Lancet. 1963;1(7285):e87623. - PubMed
1. Pagon RA, Hall JG, Davenport SL, Aase J, Norwood TH, Hoehn HW. Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Hum Genet. 1979;31(1):54–61. - PMC - PubMed
1. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–1695. doi: 10.1056/NEJM199112123252403. - DOI - PubMed

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[1] Vattathil S, Scheet P. Extensive hidden genomic mosaicism revealed in normal tissue. Am J Hum Genet. 2016;98(3):571–578. doi: 10.1016/j.ajhg.2016.02.003. - DOI - PMC - PubMed

[2] Vattathil S, Scheet P. Extensive hidden genomic mosaicism revealed in normal tissue. Am J Hum Genet. 2016;98(3):571–578. doi: 10.1016/j.ajhg.2016.02.003. - DOI - PMC - PubMed

[3] Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14(5):307–320. - PubMed

[4] Biesecker LG, Spinner NB. A genomic view of mosaicism and human disease. Nat Rev Genet. 2013;14(5):307–320. - PubMed

[5] Zellweger H, Abbo G. Chromosomal mosaicism and mongolism. Lancet. 1963;1(7285):e87623. - PubMed

[6] Zellweger H, Abbo G. Chromosomal mosaicism and mongolism. Lancet. 1963;1(7285):e87623. - PubMed

[7] Pagon RA, Hall JG, Davenport SL, Aase J, Norwood TH, Hoehn HW. Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Hum Genet. 1979;31(1):54–61. - PMC - PubMed

[8] Pagon RA, Hall JG, Davenport SL, Aase J, Norwood TH, Hoehn HW. Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes. Am J Hum Genet. 1979;31(1):54–61. - PMC - PubMed

[9] Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–1695. doi: 10.1056/NEJM199112123252403. - DOI - PubMed

[10] Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991;325(24):1688–1695. doi: 10.1056/NEJM199112123252403. - DOI - PubMed

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

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

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