Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.

Paul Kuentz (1, 2) , Judith Saint-Onge (1, 2) , Yannis Duffourd (1, 2) , Jean-Benoît Courcet (3, 2) , Virginie Carmignac (2) , Thibaut Jouan (1, 2) , Arthur Sorlin (1, 2) , Claire Abasq Thomas (4) , Juliette Albuisson (5) , Jeanne Amiel (6) , Daniel Amram (7) , Stéphanie Arpin (8, 9) , Tania Attie-Bitach (10) , Nadia Bahi-Buisson (6) , Sébastien Barbarot (11) , Genevieve Baujat (6) , Didier Bessis (12) , Olivia Boccara , Maryse Bonniere (10) , Odile Boute (13) , Anne-Claire Bursztejn (14) , Christine Chiaverini (15) , Valérie Cormier-Daire (6) , Christine Coubes (16) , Bruno Delobel (17) , Patrick Edery (18) , Salima El Chehadeh (19) , Christine Francannet (20) , David Genevieve (16, 21) , Alice Goldenberg (22, 23) , Damien Haye (24) , Bertrand Isidor (25) , Marie-Line Jacquemont (26) , Philippe Khau van Kien (27) , Didier Lacombe (28) , Ludovic Martin (29) , Jelena Martinovic (30) , Annabel Maruani (24) , Michèle Mathieu-Dramard (31) , Juliette Mazereeuw-Hautier (32) , Caroline Michot (6) , Cyril Mignot (33) , Juliette Miquel (34) , Fanny Morice Picard (28) , Florence Petit (13) , Alice Phan (35) , Massimiliano Rossi (36) , Renaud Touraine (37) , Alain Verloes (38) , Marie Vincent (25) , Catherine Vincent-Delorme (13) , Sandra Whalen , Marjolaine Willems (16) , Nathalie Marle (1, 2) , Daphne Lehalle (2, 1) , Julien Thevenon (2, 1) , Christel Thauvin-Robinet (1, 2, 3) , Laurence Olivier-Faivre (1) , Pierre Vabres (39, 1, 2) , Jean-Baptiste Riviere (40, 2)

1 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
2 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
3 Service de pédiatrie (CHU de Dijon)
4 CHU - BREST - Hôpital Morvan - CHRU de Brest
5 HEGP - Hôpital Européen Georges Pompidou [APHP]
6 Service de Génétique Médicale [CHU Necker]
7 CHIC - Centre Hospitalier Intercommunal de Créteil
8 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
9 Service de génétique [Tours]
10 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
11 Service de dermatologie [Nantes]
12 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
13 Service de Génétique Médicale [Lille]
14 Service de Dermatologie et Allergologie [CHRU Nancy]
15 Service de Dermatologie [Nice]
16 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
17 GHICL - Groupe Hospitalier de l'Institut Catholique de Lille
18 HCL - Hospices Civils de Lyon
19 Laboratoire de Diagnostic Génétique [CHU Strasbourg]
20 Service de Génétique Médicale [CHU Clermont-Ferrand]
21 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
22 Service de génétique [Rouen]
23 GMFC - Génétique du cancer et des maladies neuropsychiatriques
24 CHU Trousseau [Tours]
25 Service de génétique médicale - Unité de génétique clinique [Nantes]
26 Service de Génétique [CHU La Réunion]
27 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
28 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
29 CHU Angers - Centre Hospitalier Universitaire d'Angers
30 AP-HP - Hôpital Antoine Béclère [Clamart]
31 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
32 CHU Toulouse [Toulouse]
33 Centre de référence Déficiences Intellectuelles de Causes Rares [CHU Pitié-Salpétrière]
34 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
35 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
36 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
37 CHU de Saint-Etienne - Centre Hospitalier Universitaire de Saint-Etienne
38 Département de génétique [Robert Debré]
39 Service de Dermatologie (CHU de Dijon)
40 Laboratoire de cytogénétique (CHU de Dijon)

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

Mots clés: PIK3CA; Molecular diagnosis; Mosaicism; Next-generation sequencing; PIK3CA related overgrowth spectrum

Domaines: Sciences du Vivant [q-bio]; Génétique

Paul Kuentz, Judith Saint-Onge, Yannis Duffourd, Jean-Benoît Courcet, Virginie Carmignac, et al.. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.. Genetics in Medicine, 2017, 19 (9), pp.989-997. ⟨10.1038/gim.2016.220⟩. ⟨hal-01560452⟩