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.

Autor:	Mussa A; Department of Public Health and Pediatric Sciences, Università degli Studi di Torino, Torino, Italy.; Pediatric Clinical Genetics, Regina Margherita Children's Hospital, Hospital, Città della Salute e della Scienza di Torino, Torino, Italy., Leoni C; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy., Iacoviello M; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Carli D; Department of Public Health and Pediatric Sciences, Università degli Studi di Torino, Torino, Italy.; 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., Ranieri C; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Pantaleo A; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Buonuomo PS; Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital IRCCS, Roma, Italy., Bagnulo R; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Ferrero GB; Department of Clinical and Biological Sciences, Università degli Studi di Torino, Torino, Italy., Bartuli A; Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital IRCCS, Roma, Italy., Melis D; Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Fisciano, Italy., Maitz S; Clinical Pediatric Genetics Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy., Loconte DC; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Turchiano A; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Piglionica M; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., De Luisi A; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Susca FC; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Bukvic N; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Forleo C; Cardiology Unit, Department of Emergency and Organ Transplantation, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Selicorni A; Pediatric Department, ASST Lariana, Monza, Italy., Zampino G; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy., Onesimo R; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy., Cappuccio G; Department of Translational Medicine, Federico II University Hospital, Napoli, Italy., Garavelli L; Medical Genetics Unit, Mother and Child Health Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy., Novelli C; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy., Memo L; Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital of Vicenza, Vicenza, Italy., Morando C; Department of Pediatrics, Neonatal Intensive Care Unit, San Bortolo Hospital of Vicenza, Vicenza, Italy., Della Monica M; Medical Genetics Unit, Cardarelli Hospital, Napoli, Italy, Italy., Accadia M; Medical Genetics Unit, Hospital 'Cardinale G. Panico', Tricase, Italy., Capurso M; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy., Piscopo C; Medical Genetics Unit, Cardarelli Hospital, Napoli, Italy, Italy., Cereda A; Pediatric Department, ASST Papa Giovanni XXIII, Bergamo, Italy., Di Giacomo MC; Unit of Pathology and Medical Genetics, AOR Ospedale 'San Carlo', Potenza, Italy., Saletti V; Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy., Spinelli AM; Regional Coordinating Center for Rare Diseases, University Hospital, Udine, Italy, Italy., Lastella P; Centro Sovraziendale di Assistenza e Ricerca per le Malattie Rare, Internal Medicine Unit 'C. Frugoni', Ospedale Consorziale Policlinico di Bari, Bari, Italy., Tenconi R; Department of Pediatrics, Clinical Genetics, Universita degli Studi di Padova, Padova, Italy., Dvorakova V; Dermatology Clinic, Our Lady's Children's Hospital Crumlin, Dublin, Ireland., Irvine AD; Dermatology Clinic, Our Lady's Children's Hospital Crumlin, Dublin, Ireland., Resta N; Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari 'Aldo Moro', Bari, Italy nicoletta.resta@uniba.it.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2023 Feb; Vol. 60 (2), pp. 163-173. Date of Electronic Publication: 2022 Mar 07.
DOI:	10.1136/jmedgenet-2021-108093
Abstrakt:	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 . Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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