Abstract
RASA1-related disorders are vascular malformation syndromes characterized by hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. The number of cases reported is relatively small; and while the main clinical features are CMs and AVMs/AVFs, the broader phenotypic spectrum caused by variants in the RASA1 gene is still being defined. Here, we report the clinical and molecular findings in 69 unrelated cases with a RASA1 variant identified at ARUP Laboratories. Sanger sequencing and multiplex ligation-dependent probe amplification were primarily used to evaluate RASA1. Several atypical cases were evaluated using next-generation sequencing (NGS) and array-comparative genomic hybridization (aCGH). Sixty individuals had a deleterious RASA1 variant of which 29 were novel. Nine individuals had a variant of uncertain significance. Five large RASA1 deletions were detected, giving an overall deletion/duplication rate of 8.3% (5/60) among positive cases. Most (75.4%) individuals with a RASA1 variant had CMs, and 44.9% had an AVM/AVF. Clinical findings in several cases expand the RASA1 phenotype. Our data suggest that screening for large RASA1 deletions and duplications in this disorder is important and suggest that NGS multi-gene panel testing is beneficial for the molecular diagnosis of cases with complex vascular phenotypes.
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References
Revencu N, Boon LM, Mulliken JB, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29:959–65.
Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240–9.
Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15:265–9.
Hershkovitz D, Bercovich D, Sprecher E, Lapidot M. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035–40.
Larralde M, Abad M, Luna P, Hoffner M. Capillary malformation-arteriovenous malformation: a clinical review of 45 patients. Int J Dermatol. 2014;53:458–61.
Boon LM, Revencu N, Vikkula M. Capillary malformation-arteriovenous malformation and RASA1 mutations. Chichester: John Wiley & Sons Ltd; 2011.
Thiex R, Mulliken JB, Revencu N, et al. A novel association between RASA1 mutations and spinal arteriovenous anomalies. AJNR Am J Neuroradiol. 2010;31:775–9.
Bayrak-Toydemir P, Stevenson D. RASA1 related disorders. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews. Seattle: University of Washington; 2011.
Lacalm A, Fichez A, Broussin B, Abel C, Lacombe D, Guibaud L. Prenatal diagnosis of cerebral and extra-cerebral high-flow lesion revealing unknown familial CM-AVM syndrome. Ultrasound Obstet Gynecol. 2017;51:409–11. https://doi.org/10.1002/uog.17460.
Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, et al. RASA1 somatic mutation and variable expressivity in Capillary Malformation/Arteriovenous Malformation (CM/AVM) Syndrome. Am J Med Genet A. 2015;170:1450–4.
Hernandez F, Huether R, Carter L, et al. Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia. Hum Genome Var. 2015;2:15040.
Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer JF, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and molecular findings in a series of consecutive cases. Eur J Med Genet. 2012;55:91–95.
Revencu N, Boon L, Mendola A, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mut. 2013;34:1632–41.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.
Li H, Ruan J, Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008;18:1851–8.
McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.
Carr CW, Zimmerman HH, Martin CL, Vikkula M, Byrd AC, Abdul-Rahman OA. 5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C. Am J Med Genet A. 2011;155A:1640–5.
Ilari R, Agosta G, Bacino C. 5q14.3 deletion neurocutaneous syndrome: contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease. Am J Med Genet A. 2016;170:688–93.
Sayed MG, Ahmed AF, Ringold JR, et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol. 2002;9:901–6.
Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4:1073–81.
Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.
Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.
Amyere M, Revencu N, Helaers R, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136:1037–48. https://doi.org/10.1161/CIRCULATIONAHA.116.026886.
Yu J, Streicher JL, Medne L, Krantz ID, Yan AC. EPHB4 mutation implicated in capillary-malformation-arteriovenous malformation syndrome: A case report. Pediatr Dermatol. 2017;34:e227–e230. https://doi.org/10.1111/pde.13208.
McCormick F. Ras GTPase activating protein: signal transmitter and signal terminator. Cell. 1989;56:5–8.
McDonald J, Bayrak-Toydemir P, Pyeritz R. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011;13:607–15.
Shovlin C, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91:66–67.
Acknowledgements
We thank members of the ARUP Molecular Genetics and Genomics Clinical Laboratories for assisting in the sequence analysis of these patients. We thank the ARUP Institute for Clinical and Experimental Pathology for funding this work.
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Wooderchak-Donahue, W.L., Johnson, P., McDonald, J. et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet 26, 1521–1536 (2018). https://doi.org/10.1038/s41431-018-0196-1
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DOI: https://doi.org/10.1038/s41431-018-0196-1
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