RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed.
A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing−based testing. We investigated the mutational spectrum and genotype−phenotype associations of mosaic RAS variants.
In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots.
Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
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- Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies.Am J Med Genet C Semin Med Genet. 2016; 172: 402-421https://doi.org/10.1002/ajmg.c.31531
- Cancer-associated PIK3CA mutations in overgrowth disorders.Trends Mol Med. 2018; 24: 856-870https://doi.org/10.1016/j.molmed.2018.08.003
- ISSVA classification. International Society for the Study of Vascular Anomalies.(Accessed May 22, 2022.)
- Diagnostic utility of next-generation sequencing for disorders of somatic mosaicism: a five-year cumulative cohort.Am J Hum Genet. 2019; 105: 734-746https://doi.org/10.1016/j.ajhg.2019.09.002
- Guanine nucleotide exchange factors operate by a simple allosteric competitive mechanism.Biochemistry. 2005; 44: 15423-15429https://doi.org/10.1021/bi0518601
- GTPase activating proteins: structural and functional insights 18 years after discovery.Cell Mol Life Sci. 2005; 62: 3014-3038https://doi.org/10.1007/s00018-005-5136-x
- A comprehensive survey of Ras mutations in cancer.Cancer Res. 2012; 72: 2457-2467https://doi.org/10.1158/0008-5472.CAN-11-2612
- Enhanced interpretation of 935 hotspot and non-hotspot RAS variants using evidence-based structural bioinformatics.Comput Struct Biotechnol J. 2021; 20: 117-127https://doi.org/10.1016/j.csbj.2021.12.007
- Somatic activating RAS mutations cause vascular tumors including pyogenic granuloma.J Invest Dermatol. 2015; 135: 1698-1700https://doi.org/10.1038/jid.2015.55
- Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.J Clin Invest. 2018; 128 (Published correction appears in J Clin Invest. 2018;128(11):5185. https://doi.org/10.1172/JCI98589): 1496-1508
- Epidermal, sebaceous, and melanocytic nevoid proliferations are spectrums of mosaic RASopathies.J Invest Dermatol. 2014; 134: 2493-2496https://doi.org/10.1038/jid.2014.244
- Keratinocytic epidermal nevi are associated with mosaic RAS mutations.J Med Genet. 2012; 49: 249-253https://doi.org/10.1136/jmedgenet-2011-100637
- Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.Nat Genet. 2012; 44: 783-787https://doi.org/10.1038/ng.2316
- Mosaic RASopathy due to KRAS variant G12D with segmental overgrowth and associated peripheral vascular malformations.Am J Med Genet A. 2021; 185: 3122-3128https://doi.org/10.1002/ajmg.a.62386
- Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.J Med Genet. 2006; 43: 401-405https://doi.org/10.1136/jmg.2005.040352
- Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.Am J Med Genet A. 2011; 155A: 486-507https://doi.org/10.1002/ajmg.a.33857
Gripp KW, Rauen KA. Costello syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al, eds. GeneReviews® [Internet]. University of Washington; 1993-2022.
- Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndrome.Hum Mol Genet. 2013; 22: 1643-1653https://doi.org/10.1093/hmg/ddt014
- Recurrent duplication mutation in HRAS causing mild Costello syndrome in a Chinese patient.Clin Exp Dermatol. 2015; 40: 404-407https://doi.org/10.1111/ced.12571
- Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS.Sci Rep. 2019; 9: 8239https://doi.org/10.1038/s41598-019-44584-7
- The novel duplication HRAS c.186_206dup p.(Glu62_Arg68dup): clinical and functional aspects.Eur J Hum Genet. 2020; 28: 1548-1554https://doi.org/10.1038/s41431-020-0662-4
- Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome.Hum Mutat. 2022; 43: 3-15https://doi.org/10.1002/humu.24287
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
Published online: November 29, 2022
Accepted: November 20, 2022
Received in revised form: November 14, 2022
Received: July 1, 2022
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.