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J Invest Dermatol. 2018 Apr;138(4):957-967. doi: 10.1016/j.jid.2017.10.033. Epub 2017 Nov 22.

Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics.

Author information

1
Department of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
2
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
3
Department of Dermatology, Children's Hospital of Philadelphia, Pennsylvania, USA.
4
Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
5
Department of Pediatrics, Division of Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
6
Department of Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
7
Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
8
Department of Dermatology, University of Iowa, Iowa City, Iowa, USA.
9
Department of Pathology & Immunology, Genomics and Pathology Services, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA.
10
Department of Dermatology, Rady Children's Hospital-San Diego, University of California San Diego, San Diego, California, USA.
11
Department of Dermatology, University of California Los Angeles, Los Angeles, California, USA.
12
Department of Plastic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
13
Department of Pediatrics, Akron Children's Hospital, Akron, OH, USA.
14
Department of Dermatology, Loyola University Medical Center, Maywood, Illinois, USA.
15
Department of Orthopedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
16
Department of Pediatric Dermatology, Hospital Sainte-Justine, Montreal, Quebec, Canada.
17
Department of Dermatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
18
Department of Dermatology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
19
Department of Dermatology, University of California San Francisco, San Francisco, California, USA.
20
Department of Dermatology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
21
Department of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address: bdrolet@mcw.edu.

Abstract

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

PMID:
29174369
DOI:
10.1016/j.jid.2017.10.033
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