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Detecting mosaic variants in patients with somatic overgrowth syndromes using cell-free circulating DNA and deep sequencing
  1. Wei Shen1,2,
  2. Josue Flores-Daboub3,
  3. Dave Viskochil3,
  4. Sarah L. Dugan3,
  5. Hunter D. Best1,2,3,
  6. Rong Mao1,2
  1. 1 Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
  2. 2 ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, ARUP Laboratories, Salt Lake City, Utah, USA
  3. 3 Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA
  1. Correspondence to Dr Wei Shen, Pathology, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; shen.wei{at}

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Somatic overgrowth syndromes (SOS) comprise a group of disorders that are characterised by excessive tissue growth caused by mosaic variants in genes involved in regulating cell growth/cell cycle. For example, somatic mutations in PIK3CA/AKT1 pathway cause multiple asymmetric overgrowth disorders including CLOVES syndrome, Klippel–Trenaunay syndrome, megalencephaly capillary malformation syndrome, Proteus syndrome, megalencephaly polymicrogyria polydactyly hydrocephalus syndrome and hemihyperplasia multiple lipomatosis. These disorders are characterised by segmental overgrowth with lymphatic or vascular malformations, epidermal nevi, skeletal abnormalities, fibroadipose overgrowth, megalencephaly and increased risk for cancer. Due to the somatic nature of these disorders, detection of the underlying mutations has been challenging, as it requires genetic testing to be performed on affected tissues collected surgically. This has also contributed to underdiagnosis of these conditions.

The mutation spectrum of SOS overlaps with that in cancer. For example, besides PIK3CA and AKT1, somatic mutations in many other common oncogenes, including MTOR, GNAS, GNAQ, GNA11, NRAS, IDH1, IDH2, MAP2K1, SMO and so on, are identified in various SOS.1–9 This indicates that these disorders and cancer share the same molecular mechanisms that result in excessive cellular proliferation. Furthermore, targeted therapies are either available or under investigation in clinical trials for some of the pathways. Identification of actionable …

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  • Contributors WS, HB and RM designed the study, performed sequencing, analysed and interpreted data, and wrote the manuscript. JFD, DV and SLD contributed to the study design and recruited the patients.

  • Funding This study was funded by ARUP Institute for Clinical and Experimental Pathology.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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