A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

Ying Chen Claire Hou; Michael J. Evenson; Meagan M. Corliss; Lily Mahapatra; Ali Aldawood; David F. Carpentieri; Sarah L. Chamlin; Ann M. Kulungowski; Suneeta Madan-Khetarpal; Jessica Sebastian; Mitchell A. Pet; Carrie C. Coughlin; Marcia C. Willing; Gregory D. Pearson; Bhuvana A. Setty; Zaki El-Haffaf; Catherine E. Cottrell; Bijal A. Parikh; Kilannin Krysiak; Molly C. Schroeder; Jonathan W. Heusel; Julie A. Neidich; Yang Cao

doi:10.1016/j.gim.2022.11.016

A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

Ying Chen Claire Hou, Michael J. Evenson, Meagan M. Corliss, Lily Mahapatra, Ali Aldawood, David F. Carpentieri, Sarah L. Chamlin, Ann M. Kulungowski, Suneeta Madan-Khetarpal, Jessica Sebastian, Mitchell A. Pet, Carrie C. Coughlin, Marcia C. Willing, Gregory D. Pearson, Bhuvana A. Setty, Zaki El-Haffaf, Catherine E. Cottrell, Bijal A. Parikh, Kilannin Krysiak, Molly C. SchroederJonathan W. Heusel, Julie A. Neidich, Yang Cao^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

Original language	English (US)
Article number	100348
Journal	Genetics in Medicine
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.gim.2022.11.016
State	Published - Mar 2023

Funding

We thank the patients, families, and clinicians involved in the clinical management. There was no funding for this study. Conceptualization: Y.-C.C.H. Y.C.; Data Curation: L.M. D.F.C. S.L.C. A.M.K. S.M.-K. J.S. M.A.P. C.C.C. M.C.W. G.D.P. B.A.S. Z.E.-H.; Formal Analysis: Y.-C.C.H. M.J.E. M.M.C. A.A. C.E.C. B.A.P. K.K. M.C.S. J.W.H. J.A.N. Y.C.; Investigation: Y.-C.C.H. M.J.E.; Methodology: C.E.C. B.A.P. K.K. M.C.S. J.W.H. J.A.N. Y.C.; Project Administration: M.M.C.; Writing-original draft: Y.-C.C.H.; Supervision: Y.C.; Visualization: Y.-C.C.H. K.K.; Writing-review and editing: Y.-C.C.H. M.J.E. M.M.C. L.M. A.A. D.F.C. S.L.C. A.M.K. S.M.-K. J.S. M.A.P. C.C.C. M.C.W. G.D.P. B.A.S. Z.E.-H. C.E.C. B.A.P. K.K. M.C.S. J.W.H. J.A.N. Y.C. The study protocol (institutional review board number: 202103225) was approved by the Institutional Review Board of Washington University School of Medicine in St. Louis. These data were collected during clinical testing. The individual-level data were deidentified. Informed consent and permission were obtained to publish patients’ photos and images. The authors declare no conflicts of interest.

Keywords

Disorders of somatic mosaicism
HRAS
In-frame insertions
KRAS
RAS

ASJC Scopus subject areas

Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.gim.2022.11.016

Cite this

Claire Hou, Y. C., Evenson, M. J., Corliss, M. M., Mahapatra, L., Aldawood, A., Carpentieri, D. F., Chamlin, S. L., Kulungowski, A. M., Madan-Khetarpal, S., Sebastian, J., Pet, M. A., Coughlin, C. C., Willing, M. C., Pearson, G. D., Setty, B. A., El-Haffaf, Z., Cottrell, C. E., Parikh, B. A., Krysiak, K., ... Cao, Y. (2023). A comparative analysis of RAS variants in patients with disorders of somatic mosaicism. Genetics in Medicine, 25(3), Article 100348. https://doi.org/10.1016/j.gim.2022.11.016

@article{29942fd109984f29b62a919fd2467e4a,

title = "A comparative analysis of RAS variants in patients with disorders of somatic mosaicism",

abstract = "Purpose: 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. Methods: 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. Results: 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. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.",

keywords = "Disorders of somatic mosaicism, HRAS, In-frame insertions, KRAS, RAS",

author = "{Claire Hou}, {Ying Chen} and Evenson, {Michael J.} and Corliss, {Meagan M.} and Lily Mahapatra and Ali Aldawood and Carpentieri, {David F.} and Chamlin, {Sarah L.} and Kulungowski, {Ann M.} and Suneeta Madan-Khetarpal and Jessica Sebastian and Pet, {Mitchell A.} and Coughlin, {Carrie C.} and Willing, {Marcia C.} and Pearson, {Gregory D.} and Setty, {Bhuvana A.} and Zaki El-Haffaf and Cottrell, {Catherine E.} and Parikh, {Bijal A.} and Kilannin Krysiak and Schroeder, {Molly C.} and Heusel, {Jonathan W.} and Neidich, {Julie A.} and Yang Cao",

note = "Publisher Copyright: {\textcopyright} 2022 American College of Medical Genetics and Genomics",

year = "2023",

month = mar,

doi = "10.1016/j.gim.2022.11.016",

language = "English (US)",

volume = "25",

journal = "Genetics in Medicine",

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Claire Hou, YC, Evenson, MJ, Corliss, MM, Mahapatra, L, Aldawood, A, Carpentieri, DF, Chamlin, SL, Kulungowski, AM, Madan-Khetarpal, S, Sebastian, J, Pet, MA, Coughlin, CC, Willing, MC, Pearson, GD, Setty, BA, El-Haffaf, Z, Cottrell, CE, Parikh, BA, Krysiak, K, Schroeder, MC, Heusel, JW, Neidich, JA & Cao, Y 2023, 'A comparative analysis of RAS variants in patients with disorders of somatic mosaicism', Genetics in Medicine, vol. 25, no. 3, 100348. https://doi.org/10.1016/j.gim.2022.11.016

TY - JOUR

T1 - A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

AU - Claire Hou, Ying Chen

AU - Evenson, Michael J.

AU - Corliss, Meagan M.

AU - Mahapatra, Lily

AU - Aldawood, Ali

AU - Carpentieri, David F.

AU - Chamlin, Sarah L.

AU - Kulungowski, Ann M.

AU - Madan-Khetarpal, Suneeta

AU - Sebastian, Jessica

AU - Pet, Mitchell A.

AU - Coughlin, Carrie C.

AU - Willing, Marcia C.

AU - Pearson, Gregory D.

AU - Setty, Bhuvana A.

AU - El-Haffaf, Zaki

AU - Cottrell, Catherine E.

AU - Parikh, Bijal A.

AU - Krysiak, Kilannin

AU - Schroeder, Molly C.

AU - Heusel, Jonathan W.

AU - Neidich, Julie A.

AU - Cao, Yang

PY - 2023/3

Y1 - 2023/3

N2 - Purpose: 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. Methods: 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. Results: 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. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

AB - Purpose: 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. Methods: 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. Results: 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. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.

KW - Disorders of somatic mosaicism

KW - HRAS

KW - In-frame insertions

KW - KRAS

KW - RAS

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A comparative analysis of RAS variants in patients with disorders of somatic mosaicism

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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