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

作者：Kuentz Paul; St Onge Judith; Duffourd Yannis; Courcet Jean Benoit; Carmignac Virginie; Jouan Thibaud; Sorlin Arthur; Abasq Thomas Claire; Albuisson Juliette; Amiel Jeanne; Amram Daniel; Arpin Stephanie; Attie Bitach Tania; Bahi Buisson Nadia; Barbarot Sebastien; Baujat Genevieve; Bessis Didier; Boccara Olivia; Bonniere Maryse; Boute Odile; Bursztejn Anne Claire; Chiaverini Christine; Cormier Daire Valerie; Coubes Christine; Delobel Bruno; Edery Patrick

来源：Genetics in Medicine, 2017, 19(9): 989-997.

DOI：10.1038/gim.2016.220

• molecular diagnosis
• mosaicism
• next-generation sequencing
• PIK3CA
• PIK3CA-related overgrowth spectrum

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 x 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 x 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.

• 出版日期2017-9
• 单位McGill