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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 
Abstract : 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
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01560452
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Soumis le : mardi 11 juillet 2017 - 15:37:29
Dernière modification le : samedi 24 septembre 2022 - 15:04:06

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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, Nature Publishing Group, 2017, 19 (9), pp.989-997. ⟨10.1038/gim.2016.220⟩. ⟨hal-01560452⟩

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