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

• Published in: Genetics in medicine Vol. 19; no. 9; pp. 989 - 997
• Main Authors: Kuentz, Paul, St-Onge, Judith, Duffourd, Yannis, Courcet, Jean-Benoît, Carmignac, Virginie, Jouan, Thibaud, Sorlin, Arthur, Abasq-Thomas, Claire, Albuisson, Juliette, Amiel, Jeanne, Amram, Daniel, Arpin, Stéphanie, Attie-Bitach, Tania, Bahi-Buisson, Nadia, Barbarot, Sébastien, Baujat, Geneviève, Bessis, Didier, Boccara, Olivia, Bonnière, Maryse, Boute, Odile, Bursztejn, Anne-Claire, Chiaverini, Christine, Cormier-Daire, Valérie, Coubes, Christine, Delobel, Bruno, Edery, Patrick, Chehadeh, Salima El, Francannet, Christine, Geneviève, David, Goldenberg, Alice, Haye, Damien, Isidor, Bertrand, Jacquemont, Marie-Line, Khau Van Kien, Philippe, Lacombe, Didier, Martin, Ludovic, Martinovic, Jelena, Maruani, Annabel, Mathieu-Dramard, Michèle, Mazereeuw-Hautier, Juliette, Michot, Caroline, Mignot, Cyril, Miquel, Juliette, Morice-Picard, Fanny, Petit, Florence, Phan, Alice, Rossi, Massimiliano, Touraine, Renaud, Verloes, Alain, Vincent, Marie, Vincent-Delorme, Catherine, Whalen, Sandra, Willems, Marjolaine, Marle, Nathalie, Lehalle, Daphné, Thevenon, Julien, Thauvin-Robinet, Christel, Hadj-Rabia, Smaïl, Faivre, Laurence, Vabres, Pierre, Rivière, Jean-Baptiste
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2017; Elsevier Limited; Nature Publishing Group
• Subjects: 631/208/1516; 631/208/457/649; 631/208/514/2254; 692/700/139/1512; Adolescent; Adult; Alleles; Amino Acid Substitution; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Disease Management; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic testing; Genetic Testing - methods; Genetics; Genotype; Growth Disorders - diagnosis; Growth Disorders - genetics; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Infant; Infant, Newborn; Laboratory Medicine; Life Sciences; Male; Mosaicism; Mutation; original-research-article; Phenotype; Prenatal Diagnosis; Sequence Analysis, DNA; Young Adult; related overgrowth spectrum; next-generation sequencing; mosaicism; molecular diagnosis; Mosaicism; Molecular diagnosis; Next-generation sequencing; PIK3CA; PIK3CA related overgrowth spectrum
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/gim.2016.220

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