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Original research
Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants
  1. Alessandro Mussa1,2,
  2. Chiara Leoni3,
  3. Matteo Iacoviello4,
  4. Diana Carli1,5,
  5. Carlotta Ranieri4,
  6. Antonino Pantaleo4,
  7. Paola Sabrina Buonuomo6,
  8. Rosanna Bagnulo4,
  9. Giovanni Battista Ferrero7,
  10. Andrea Bartuli6,
  11. Daniela Melis8,
  12. Silvia Maitz9,
  13. Daria Carmela Loconte4,
  14. Antonella Turchiano4,
  15. Marilidia Piglionica4,
  16. Annunziata De Luisi4,
  17. Francesco Claudio Susca4,
  18. Nenad Bukvic4,
  19. Cinzia Forleo10,
  20. Angelo Selicorni11,
  21. Giuseppe Zampino3,
  22. Roberta Onesimo3,
  23. Gerarda Cappuccio12,
  24. Livia Garavelli13,
  25. Chiara Novelli14,
  26. Luigi Memo15,
  27. Carla Morando15,
  28. Matteo Della Monica16,
  29. Maria Accadia17,
  30. Martina Capurso4,
  31. Carmelo Piscopo16,
  32. Anna Cereda18,
  33. Marilena Carmela Di Giacomo19,
  34. Veronica Saletti20,
  35. Alessandro Mauro Spinelli21,
  36. Patrizia Lastella22,
  37. Romano Tenconi23,
  38. Veronika Dvorakova24,
  39. Alan D Irvine24,
  40. Nicoletta Resta4
  1. 1 Department of Public Health and Pediatric Sciences, Università degli Studi di Torino, Torino, Italy
  2. 2 Pediatric Clinical Genetics, Regina Margherita Children’s Hospital, Hospital, Città della Salute e della Scienza di Torino, Torino, Italy
  3. 3 Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
  4. 4 Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari “Aldo Moro”, Bari, Italy
  5. 5 Pediatric Onco-Hematology, Stem Cell Transplantation and Cell Therapy Division, Regina Margherita Children's Hospital, Città Della Salute e Della Scienza di Torino, Torino, Italy
  6. 6 Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital IRCCS, Roma, Italy
  7. 7 Department of Clinical and Biological Sciences, Università degli Studi di Torino, Torino, Italy
  8. 8 Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Fisciano, Italy
  9. 9 Clinical Pediatric Genetics Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy
  10. 10 Cardiology Unit, Department of Emergency and Organ Transplantation, Università degli Studi di Bari "Aldo Moro", Bari, Italy
  11. 11 Pediatric Department, ASST Lariana, Monza, Italy
  12. 12 Department of Translational Medicine, Federico II University Hospital, Napoli, Italy
  13. 13 Medical Genetics Unit, Mother and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
  14. 14 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy
  15. 15 Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital of Vicenza, Vicenza, Italy
  16. 16 Medical Genetics Unit, Cardarelli Hospital, Napoli, Italy, Italy
  17. 17 Medical Genetics Unit, Hospital "Cardinale G. Panico", Tricase, Italy
  18. 18 Pediatric Department, ASST Papa Giovanni XXIII, Bergamo, Italy
  19. 19 Unit of Pathology and Medical Genetics, AOR Ospedale "San Carlo", Potenza, Italy
  20. 20 Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  21. 21 Regional Coordinating Center for Rare Diseases, University Hospital, Udine, Italy, Italy
  22. 22 Centro Sovraziendale di Assistenza e Ricerca per le Malattie Rare, Internal Medicine Unit 'C. Frugoni', Ospedale Consorziale Policlinico di Bari, Bari, Italy
  23. 23 Department of Pediatrics, Clinical Genetics, Universita degli Studi di Padova, Padova, Italy
  24. 24 Dermatology Clinic, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
  1. Correspondence to Professor Nicoletta Resta, Unit of Medical Genetics, Università degli Studi di Bari Aldo Moro, 70124 Bari, Puglia, Italy; nicoletta.resta{at}


Background Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture.

Methods We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed.

Results 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK.

Conclusion We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

  • genetic testing
  • genotype
  • molecular medicine
  • sequence analysis, DNA
  • phenotype

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. not applicable.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. not applicable.

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  • Contributors Conceptualisation: NR, AM, CL. Data curation: NR, AM, CL, DC, CR. Formal analysis: NR, AM, CL, DC. Methodology: NR, AM, CL, MI, DC, CR, AP, PSB, RB, GBF, AB, DM, SM, DL, AT, MP, ADL, FCS, NB, CF, AS, GZ, GC, LG, CN, LM, CM, MDM, MA, MC, AC, MCDG, VS, AMS, PL, RT, VD. Investigation: NR, AM, CL, MI, DC, CR, AP, PSB, RB, GBF, AB, DM, SM, DL, AT, MP, ADL, FCS, NB, CF, AS, GZ, GC, LG, CN, LM, CM, MDM, MA, MC, AC, MCDG, VS, AMS, PL, RT, VD. Resources: NR, AM, MI, DC, CR, AP, PSB, RB, GBF, AB, CP, RO, DM, SM, DL, AT, MP, ADL, FCS, NB, CF, AS, GZ, GC, LG, CN, LM, CM, MDM, MA, MC, AC, MCDG, VS, AMS, PL, RT, VD. Validation: NR, AM, CL, DC, ADI. Visualisation: NR, AM, MI, AP, DC. Supervision NR. Writing—original draft: NR, AM, DC. Writing—review and editing: NR, AM, CL, DC, ADI. Guarantor: NR.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.