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Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel\u2013Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation\u2010polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain\u2010of\u2010function variants in <jats:italic>PIK3CA<\/jats:italic> as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic <jats:italic>PIK3CA<\/jats:italic> variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low\u2010level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.<\/jats:p>","DOI":"10.1002\/ajmg.a.63466","type":"journal-article","created":{"date-parts":[[2023,11,11]],"date-time":"2023-11-11T02:24:08Z","timestamp":1699669448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular characterization of 13 patients with <scp><i>PIK3CA<\/i><\/scp>\u2010related overgrowth spectrum using a targeted deep sequencing approach"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-1371","authenticated-orcid":false,"given":"Leanne","family":"de Kock","sequence":"first","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute  Ottawa Ontario Canada"},{"name":"Department of Pediatrics University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-3758","authenticated-orcid":false,"given":"Alexanne","family":"Cuillerier","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute  Ottawa Ontario Canada"},{"name":"Department of Pediatrics University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Couse","sequence":"additional","affiliation":[{"name":"The Centre for Computational Medicine the Hospital for Sick Children (SickKids) Research Institute  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1957-9820","authenticated-orcid":false,"given":"Taila","family":"Hartley","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Mears","sequence":"additional","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois P.","family":"Bernier","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Medical Genetics Alberta Children's Hospital  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert E.","family":"Chudley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences University of Manitoba  Winnipeg Manitoba Canada"},{"name":"Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9673-795X","authenticated-orcid":false,"given":"Patrick","family":"Frosk","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences University of Manitoba  Winnipeg Manitoba Canada"},{"name":"Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Nikkel","sequence":"additional","affiliation":[{"name":"Provincial Medical Genetics Program BC Women's Hospital  Vancouver British Columbia Canada"},{"name":"Department of Medical Genetics University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9881-5467","authenticated-orcid":false,"given":"A. 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