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 T. Jouan 1, 2 Arthur Sorlin 1, 2 Daphne Lehalle 2, 1 Julien Thevenon 2, 1 Christel Thauvin-Robinet 1, 2, 3 Laurence Olivier-Faivre 1 Pierre Vabres 4, 1, 2 Jean-Baptiste Riviere 5, 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 Service de Dermatologie (CHU de Dijon)
5 Laboratoire de cytogénétique (CHU de Dijon)
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
Keywords : PIK3CA
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Genetics in Medicine, Nature Publishing Group, 2017, 〈http://www.nature.com〉. 〈10.1038/gim.2016.220〉
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Contributeur : Gad - Université de Bourgogne <>
Soumis le : mardi 11 juillet 2017 - 15:37:29
Dernière modification le : jeudi 20 septembre 2018 - 16:13:42

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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, 〈http://www.nature.com〉. 〈10.1038/gim.2016.220〉. 〈hal-01560452〉

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