Profiling PIK3CA variants in disorders of somatic mosaicism
Purpose: Variants in PIK3CA (encoding p110α; the catalytic subunit of PI3K) characterize some disorders of somatic mosaicism (DoSM) conditions with clinical features, including sporadic overgrowth and vascular malformations. Here, we profile PIK3CA variants in DoSM. Methods: We applied a next-genera...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Genetics in Medicine Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774423008245 |
| _version_ | 1797341908882685952 |
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| author | Bahareh A. Mojarad Patricia V. Hernandez Michael J. Evenson Meagan M. Corliss Sarah L. Stein Amy Theos Carrie C. Coughlin Bryan Sisk Maithilee Menezes Molly C. Schroeder Jonathan W. Heusel Julie A. Neidich Yang Cao |
| author_facet | Bahareh A. Mojarad Patricia V. Hernandez Michael J. Evenson Meagan M. Corliss Sarah L. Stein Amy Theos Carrie C. Coughlin Bryan Sisk Maithilee Menezes Molly C. Schroeder Jonathan W. Heusel Julie A. Neidich Yang Cao |
| author_sort | Bahareh A. Mojarad |
| collection | DOAJ |
| description | Purpose: Variants in PIK3CA (encoding p110α; the catalytic subunit of PI3K) characterize some disorders of somatic mosaicism (DoSM) conditions with clinical features, including sporadic overgrowth and vascular malformations. Here, we profile PIK3CA variants in DoSM. Methods: We applied a next-generation, sequencing-based, laboratory-developed test, using an average coverage of approximately 2000× for up to 37 genes associated with DoSM, on a cohort of 1197 patients with DoSM referred for clinical genomics services between 2013 and 2022. Results: We identified clinically reportable variants in 747 (62.4%) individuals in this cohort. Notably, 371 clinically reportable variants in PIK3CA were identified in 368 patients, constituting approximately 49.2% of all patients with reportable findings. Variants in the C2 domain of p110α are enriched in DoSM (this cohort) compared with those of cancer (Catalogue of Somatic Mutations in Cancer [COSMIC] database), highlighting the role of the C2 domain in driving uncontrolled cell proliferation in DoSM. Furthermore, we report 17 novel variants in PIK3CA that are not previously reported in DoSM and describe clinical presentation correlation for 4 novel variants. Conclusion: Our findings from the largest single-center cohort of patients with DoSM expand the spectrum of variants in PIK3CA and shed light on the less-studied role of the C2 domain in the pathogenesis of DoSM. |
| first_indexed | 2024-03-08T10:25:46Z |
| format | Article |
| id | doaj.art-8ea711a209f14e6298e7a8cde88994e4 |
| institution | Directory Open Access Journal |
| issn | 2949-7744 |
| language | English |
| last_indexed | 2024-03-08T10:25:46Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj.art-8ea711a209f14e6298e7a8cde88994e42024-01-27T07:13:31ZengElsevierGenetics in Medicine Open2949-77442023-01-0111100815Profiling PIK3CA variants in disorders of somatic mosaicismBahareh A. Mojarad0Patricia V. Hernandez1Michael J. Evenson2Meagan M. Corliss3Sarah L. Stein4Amy Theos5Carrie C. Coughlin6Bryan Sisk7Maithilee Menezes8Molly C. Schroeder9Jonathan W. Heusel10Julie A. Neidich11Yang Cao12Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MOSection of Dermatology, Departments of Medicine and Pediatrics, University of Chicago, Chicago, ILDepartment of Dermatology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, ALDivision of Dermatology, Departments of Medicine and Pediatrics, Washington University School of Medicine, St. Louis, MODivision of Pediatric Hematology and Oncology, Department of Pediatrics, and Department of Medicine, Oncology and Bioethics Research Center, Washington University in St. Louis School of Medicine, St. Louis, MODivision of Pediatric Otolaryngology, Department of Otolaryngology, Head and Neck Surgery, Washington University in St. Louis School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO; Department of Genetics, Washington University School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO; Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MODepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO; Correspondence and requests for materials should be addressed to Yang Cao, 660 South Euclid Avenue, Campus Box MSC 8118-99-02, St. Louis, MO 63110Purpose: Variants in PIK3CA (encoding p110α; the catalytic subunit of PI3K) characterize some disorders of somatic mosaicism (DoSM) conditions with clinical features, including sporadic overgrowth and vascular malformations. Here, we profile PIK3CA variants in DoSM. Methods: We applied a next-generation, sequencing-based, laboratory-developed test, using an average coverage of approximately 2000× for up to 37 genes associated with DoSM, on a cohort of 1197 patients with DoSM referred for clinical genomics services between 2013 and 2022. Results: We identified clinically reportable variants in 747 (62.4%) individuals in this cohort. Notably, 371 clinically reportable variants in PIK3CA were identified in 368 patients, constituting approximately 49.2% of all patients with reportable findings. Variants in the C2 domain of p110α are enriched in DoSM (this cohort) compared with those of cancer (Catalogue of Somatic Mutations in Cancer [COSMIC] database), highlighting the role of the C2 domain in driving uncontrolled cell proliferation in DoSM. Furthermore, we report 17 novel variants in PIK3CA that are not previously reported in DoSM and describe clinical presentation correlation for 4 novel variants. Conclusion: Our findings from the largest single-center cohort of patients with DoSM expand the spectrum of variants in PIK3CA and shed light on the less-studied role of the C2 domain in the pathogenesis of DoSM.http://www.sciencedirect.com/science/article/pii/S2949774423008245NGSPIK3CAPIK3CA-related overgrowth spectrumPROSSomatic mosaicism |
| spellingShingle | Bahareh A. Mojarad Patricia V. Hernandez Michael J. Evenson Meagan M. Corliss Sarah L. Stein Amy Theos Carrie C. Coughlin Bryan Sisk Maithilee Menezes Molly C. Schroeder Jonathan W. Heusel Julie A. Neidich Yang Cao Profiling PIK3CA variants in disorders of somatic mosaicism Genetics in Medicine Open NGS PIK3CA PIK3CA-related overgrowth spectrum PROS Somatic mosaicism |
| title | Profiling PIK3CA variants in disorders of somatic mosaicism |
| title_full | Profiling PIK3CA variants in disorders of somatic mosaicism |
| title_fullStr | Profiling PIK3CA variants in disorders of somatic mosaicism |
| title_full_unstemmed | Profiling PIK3CA variants in disorders of somatic mosaicism |
| title_short | Profiling PIK3CA variants in disorders of somatic mosaicism |
| title_sort | profiling pik3ca variants in disorders of somatic mosaicism |
| topic | NGS PIK3CA PIK3CA-related overgrowth spectrum PROS Somatic mosaicism |
| url | http://www.sciencedirect.com/science/article/pii/S2949774423008245 |
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