Paul Kuentz1,2,3, Judith St-Onge1,2,4, Yannis Duffourd1,2, Jean-Benoît Courcet2,5, Virginie Carmignac1,2, Thibaud Jouan1,2, Arthur Sorlin1,2, Claire Abasq-Thomas6, Juliette Albuisson7, Jeanne Amiel8, Daniel Amram9, Stéphanie Arpin10, Tania Attie-Bitach11, Nadia Bahi-Buisson8, Sébastien Barbarot12, Geneviève Baujat8, Didier Bessis13, Olivia Boccara14, Maryse Bonnière11, Odile Boute15, Anne-Claire Bursztejn16, Christine Chiaverini17, Valérie Cormier-Daire8, Christine Coubes18, Bruno Delobel19, Patrick Edery20, Salima El Chehadeh21, Christine Francannet22, David Geneviève18, Alice Goldenberg23, Damien Haye24, Bertrand Isidor25, Marie-Line Jacquemont26, Philippe Khau Van Kien27, Didier Lacombe28, Ludovic Martin29, Jelena Martinovic30, Annabel Maruani31, Michèle Mathieu-Dramard32, Juliette Mazereeuw-Hautier33, Caroline Michot8, Cyril Mignot34, Juliette Miquel35, Fanny Morice-Picard28, Florence Petit15, Alice Phan36, Massimiliano Rossi20, Renaud Touraine37, Alain Verloes38, Marie Vincent25, Catherine Vincent-Delorme15, Sandra Whalen39, Marjolaine Willems18, Nathalie Marle1,2,40, Daphné Lehalle1,2,5, Julien Thevenon1,2,5, Christel Thauvin-Robinet1,2,5, Smaïl Hadj-Rabia14, Laurence Faivre1,2,5, Pierre Vabres1,2,41, Jean-Baptiste Rivière1,2,4,42. 1. Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France. 2. Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université Bourgogne Franche-Comté, Dijon, France. 3. Génétique Biologique Histologie, CHRU de Besançon, Besançon, France. 4. Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 5. Service de Pédiatrie 1 et de Génétique Médicale, CHU Dijon Bourgogne, Dijon, France. 6. Département de Pédiatrie et Génétique Médicale, CHU Brest Morvan, Brest, France. 7. Centre de Référence des Maladies Vasculaires Rares, Hôpital Européen Georges Pompidou, Paris, France. 8. Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Paris, France. 9. Unité de Génétique Clinique, CHI de Créteil, Créteil, France. 10. Service de Génétique Clinique, CHRU de Tours, Tours, France. 11. Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France. 12. Service de Dermatologie, CHU de Nantes, Nantes, France. 13. Département de Dermatologie, CHRU de Montpellier, Montpellier, France. 14. Department of Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 15. Service de Génétique Clinique, CHU Lille, Lille, France. 16. Service de Dermatologie, CHU de Nancy, Nancy, France. 17. Service de Dermatologie, CHU de Nice, Nice, France. 18. Département de Génétique Médicale, Maladies rares et Médecine Personnalisée, CHRU de Montpellier, Montpellier, France. 19. Centre de Génétique Chromosomique, GH de l'Institut Catholique de Lille, Lille, France. 20. Genetics Department, Hospices Civils de Lyon and GENDEV team, Lyon Neuroscience Research Centre, INSERM U1028, CNRS UMR 5292, Claude Bernard Lyon 1 University, Lyon, France. 21. Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France. 22. Service de Génétique Médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France. 23. Service de Génétique, CHU de Rouen et Inserm U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France. 24. Service de Pédiatrie, CHU de Tours, Tours, France. 25. Service de Génétique Médicale, CHU de Nantes, Nantes, France. 26. Unité de Génétique Médicale, CHU de la Réunion, Saint-Pierre, France. 27. Unité de Génétique Médicale et Cytogénétique, CHU de Nîmes, Nîmes, France. 28. INSERM U1211, Université de Bordeaux, Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France. 29. Service de Dermatologie, CHU d'Angers, Angers, France. 30. Unité de Fœtopathologie, APHP, Hôpital Antoine-Béclère, Clamart, France. 31. Université François-Rabelais, Service de Dermatologie, Unité de Dermatologie Pédiatrique, CIC Inserm 1415, Tours, France. 32. Centre d'Activité de Génétique Clinique et Oncogénétique, CHU d'Amiens, Amiens, France. 33. Centre de Référence des Maladies Rares de la Peau, CHU de Toulouse, Toulouse, France. 34. APHP, Département de Génétique et Cytogénétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, GRC UPMC Déficiences Intellectuelles et Autisme, GH La Pitié Salpêtrière, Paris, France. 35. Service de Pédiatrie Générale, CHU de la Réunion, Saint-Pierre, France. 36. Service de Dermatologie, CHU de Lyon, Lyon, France. 37. Service de Génétique Clinique, CHU de Saint-Etienne, Saint-Priest-en-Jarez, France. 38. Unité Fonctionnelle de Génétique Clinique, Hôpital Robert Debré, Paris, France. 39. Unité Fonctionnelle de Génétique Clinique, Hôpital Armand-Trousseau, Paris, France. 40. Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon Bourgogne, Dijon, France. 41. Service de Dermatologie, CHU Dijon Bourgogne, Dijon, France. 42. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Abstract
PURPOSE: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. METHODS: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. RESULTS: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10-5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10-25), regardless of the phenotype. CONCLUSION: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.
PURPOSE: Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. METHODS: We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. RESULTS: We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10-5). We identified 40 different mutations and found strong oncogenic mutations more frequently in patients without brain overgrowth (50.6%) than in those with brain overgrowth (15.2%; P = 0.00055). Mutant allele levels were higher in skin and overgrown tissues than in blood and buccal samples (P = 3.9 × 10-25), regardless of the phenotype. CONCLUSION: Our data demonstrate the value of ultradeep NGS for molecular diagnosis of PROS, highlight its substantial allelic heterogeneity, and confirm that optimal diagnosis requires fresh skin or surgical samples from affected regions. Our findings may be of value in guiding future recommendations for genetic testing in PROS and other mosaic conditions.Genet Med advance online publication 02 February 2017.
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